bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-145: Pten deletion in SOX9+ cells synergizes with hepatic injury to drive tumor development in mouse liver
Authors: Zeng Ni , Kassa Anketse , Kopp Janel , He Lina , Sander Maike , Stiles Bangyan 
Published: August 2015

Abstract
Liver cancer is an extremely deadly disease ranked as the third most common cancer and the second leading cause of male cancer-related death worldwide. Among primary liver cancers, hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the two most frequent subtypes, accounting for 85-95% of the total liver cancer cases, and both types of liver cancer have been found to originate from the expansion and differentiation of tumor initiating cells (TICs). Thus, it is critically important to understand mechanisms that regulate liver TICs activation. By utilizing a Pten(loxp/loxp); Albumin-Cre+ mouse liver cancer model (L-PKO), our previous studies have confirmed the activation of TICs during liver tumorigenesis. We also found that SOX9 was expressed in both HCC and CC, suggesting that SOX9 might serve as a liver TICs marker. We thus used the Pten(loxp/loxp); SOX9-CreER+ mouse model (TIC-PKO) to study the role of PTEN in TICs during liver tumorigenesis. Liver tumor development was observed in TIC-PKO mice at the age of 12 months old, and immunohistochemical analysis revealed that the tumors were heterogeneous, indicating TICs were involved in the tumorigenesis process. In addition, treatment of DDC, which is a liver toxin and thus causes hepatocyte death, dramatically increased the incidence and led to the early onset of liver tumorigenesis in the mutant but not the control mice, suggesting that liver injury served as an essential microenvironmental niche in promoting liver tumor development. Together, our observations suggested that the PTEN signaling is critical for TICs regulation and Pten deletion synergizes with liver injury to drive both TICs activation and liver tumorigenesis.
Citation Format: Ni Zeng, Anketse Kassa, Janel Kopp, Lina He, Maike Sander, Bangyan Stiles. Pten deletion in SOX9+ cells synergizes with hepatic injury to drive tumor development in mouse liver. [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 LB-145. doi:10.1158/1538-7445.AM2015-LB-145
Abstract LB-155: Epigenetic profiling of chemotherapy sensitivity
Authors: Gurard-Levin Zachary A. , Pancaldi Vera , Wilson Laurence OW , Marangoni Elisabetta , Roman-Roman Sergio , Valencia Alfonso , Cottu Paul , Almouzni Genevieve 
Published: August 2015

Abstract
Many anti-cancer drugs act by directly binding or modifying DNA, or through indirect binding during processes that rely on the chromatin architecture. Mis-regulation of the expression of epigenetic factors may perturb chromatin organization and contribute to drug resistance mechanisms. Here, we aim to investigate the power of chromatin regulators and epigenetic factors as predictive markers for the efficacy of single chemotherapy drugs.
We exploit transcriptome data from breast cancer cell lines and a validation set comprised of breast cancer patient derived xenograft (PDX) models that are either sensitive or resistant to individual chemotherapy agents, to correlate mRNA expression of chromatin regulators to drug efficacy. We then use Random Forests, a non-parametric machine learning method, to model the cell lines’ response to different compounds. The model is then used to predict the patients’ response to each drug, identifying which genes contribute the most to the prediction. We then compare our predictive gene signature to commercially available prognostic kits.
Random Forest analysis revealed a 28-gene signature (termed EPOCH28) containing several histone chaperones, histone variants, histone modifying enzymes, among other chromatin regulators, which is highly predictive of drug efficacy. Indeed, our model accurately predicts 11 of 14 resistant PDX models and 15 out of 17 sensitive PDX models (∼ 84%), with an average confidence level of over 73%. Importantly, we find that the EPOCH28 gene signature is specific, and is thus not a general prognostic signature for patients who will benefit from any chemotherapy. In line with this, the EPOCH28 outperforms the breast cancer prognostic gene signatures of Mammaprint and Oncotype DX, suggesting that while these commercial tests may help guide clinical decisions, it will be critical to consider additional factors that can help identify which drug will be most beneficial to an individual patient.
The integration of chromatin regulators as clinical biomarkers, in particular in the context of predictive markers for the response to a single drug, will help guide clinical decisions and treatment options for breast cancer. Importantly, our approach is general and thus can be applied to other chemotherapy drugs, including those in clinical trials to develop companion diagnostics, and for other cancer types.
Citation Format: Zachary A. Gurard-Levin, Vera Pancaldi, Laurence OW Wilson, Elisabetta Marangoni, Sergio Roman-Roman, Alfonso Valencia, Paul Cottu, Genevieve Almouzni. Epigenetic profiling of chemotherapy sensitivity. [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 LB-155. doi:10.1158/1538-7445.AM2015-LB-155
Abstract LB-177: Novel approaches for improving interpretation and predictive models of comparative genomic hybridization data
Authors: Rotroff Daniel , Breen Matthew , Motsinger-Reif Alison 
Published: August 2015

Abstract
As costs of genome wide analyses decline and become more accessible, their use in both human and animal cancer studies are generating increasing information regarding underlying cancer etiology. Comparative genomic hybridization (CGH) is providing valuable information relating copy number aberrations (CNAs) to cancer mechanisms and clinical outcomes. However, challenges exist to interpreting and fully utilizing these data. First, without matched tumor and healthy tissue samples from individuals, distinguishing naturally occurring copy number variations (CNVs) from CNAs is difficult. Second, the large search space of genome wide analyses makes finding combinations of CNAs with improved predictive potential compared to single CNAs challenging. Here we provide novel methods to address these challenges associated with CGH data. Many new resources (e.g. The Cancer Genome Atlas (TCGA)), are making large volumes of genomic data publically accessible. However, most datasets do not have matched normal and tumor tissue samples between subjects. We tested matched normal and tissue samples from 30 patients with colorectal, lung, and pancreatic cancer and compared CNVs and CNAs to findings in larger, non-matched samples in TCGA. Even with limited matched samples, this approach allows for the differentiation of CNVs from CNAs discovered in analyses of non-matched samples.
In some cases, combinations of CNAs can provide improved predictive capability compared to any single CNA. However, it is computationally intractable to exhaustively test combinations of CNAs in a genome-wide study. To address this limitation, we use a novel approach for CNA feature reduction that minimizes the variance within CNA segments across subjects, and Random Forest Ensemble Classification. This approach provides CNA combinations with balanced accuracies of 83.5% and 94.9% for distinguishing 52 cases of canine ALL/AML and 71 cases of B-CLL/T-CLL, respectively. These two approaches address frequent limitations in the interpretation CGH data. Better distinguishing CNVs and interrogating CNA combinations, can provide additional information about the role of CNAs in disease mechanisms and improve treatment decisions.
Citation Format: Daniel Rotroff, Matthew Breen, Alison Motsinger-Reif. Novel approaches for improving interpretation and predictive models of comparative genomic hybridization data. [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 LB-177. doi:10.1158/1538-7445.AM2015-LB-177
Abstract LB-182: Improved survival among lung cancer patients taking antidepressants
Authors: Zingone Adriana , Brown Derek , Bowman Elise , Vidal Oscar , Neal Joel , Sage Julien , Ryan Brid M. 
Published: August 2015

Abstract
In recent years, the anti-cancer properties of several commonly used drugs have been explored, with drugs such as aspirin and beta-blockers associated with improved cancer outcomes. Emerging evidence suggests that the antidepressant family of drugs may target key pathways in cancer cells, raising the possibility that such drugs could be re-purposed for cancer treatment. Here, using the NCI-MD lung cancer study, we assessed antidepressant use in 1,098 lung cancer patients. Strikingly, antidepressant use was associated with a significant extension of lung cancer-specific survival (HR = 0.78, 95% C.I. = 0.63 - 0.97, P = 0.027) (model adjusted for age, gender, race, smoking status, pack-years of smoking, tumor stage and histology). When assessing distinct classes of antidepressants, we observed that NDRIs (norepinephrine and dopamine reuptake inhibitors) and TCAs (tricyclic antidepressants) were specifically associated with extended survival: TCA HR = 0.40, 95% C.I. = 0.18 - 0.91, P = 0.028 and NDRI HR = 0.61, 95% C.I. = 0.39 - 0.95, P = 0.027). In contrast, SRIs (serotonin reuptake inhibitors) were linked with worse survival (HR 1.94 95% C.I. 1.10 - 2.42, P = 0.023). Importantly, the extended survival time associated with antidepressants was not associated with the typical indications for these drugs, suggestive of a direct effect on lung cancer cells. In addition, as we assessed lung cancer-specific survival we conducted a competing risks analysis, the results of which showed that both NDRIs and TCAs were associated with lung cancer survival (fully adjusted model NDRI, HR: 0.63, 95% C.I. 0.40 - 1.00, P = 0.05) (fully adjusted model TCA, HR: 0.36, 95% C.I. 0.17 - 0.76, P = 0.007). We provide strong evidence that lung cancer patients taking antidepressants, particularly NDRIs and TCAs, have a significantly prolonged survival. Considering the manageable and largely tolerable side effects of antidepressants, and the low cost of these drugs, these results indicate that repositioning antidepressants as adjunct therapeutics with chemotherapy may have a rapid and significant translational impact for lung cancer patients.
Citation Format: Adriana Zingone, Derek Brown, Elise Bowman, Oscar Vidal, Joel Neal, Julien Sage, Brid M. Ryan. Improved survival among lung cancer patients taking antidepressants. [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 LB-182. doi:10.1158/1538-7445.AM2015-LB-182
Abstract LB-205: Myeloid cells are required to establish an immune-suppressive regulatory network in pancreatic cancer by activating the PD-1/PD-L1 checkpoint
Authors: ZHANG YAQING , MATHEW ESHA , MENDEZ FLOR , FLANNAGAN KEVIN , SIMEONE DIANE , PASCA DI MAGLIANO MARINA 
Published: August 2015

Abstract
Background: Pancreatic cancer is characterized by the accumulation of a fibro-inflammatory stroma. Myeloid cells are a predominant population within the stroma. Different myeloid cell subsets have been correlated with tumor promotion and unmasking of anti-tumor immunity.
Objective: The goal of this study was to determine the effect of myeloid cell depletion on the onset and progression of pancreatic cancer, and to understand the relationship between myeloid cells and T cell infiltration and activity within the pancreatic cancer microenvironment.
Methods: Primary mouse pancreatic cancer cells were transplanted in CD11b-DTR mice. CD11b+ cells (most myeloid cell populations) were depleted by Diphtheria Toxin treatment; either at the time of tumor implantation or after tumors had formed.
Results Depletion of myeloid cells delayed tumor initiation. In pre-established tumors, myeloid cell depletion resulted in arrest of growth or tumor regression. We observed that tumor regression was dependent myeloid cell-mediated blockade of CD8+ T cell anti-tumor activity. We investigated the mechanism of this inhibition. We found that myeloid cells regulate expression of the immune checkpoint ligand Programmed death-ligand 1 (PD-L1) in the tumor cells in an EGFR/MAPK dependent manner.
Conclusions: Our results show that myeloid cells regulate a complex network of signals that ensure immune suppression within the pancreatic cancer microenvironment. Moreover, we show that depletion of the myeloid cell population is sufficient to restore anti-tumor immunity mediated by CD8+ T cells, a finding with implications for the design of immune therapies for pancreatic cancer.
Citation Format: YAQING ZHANG, ESHA MATHEW, FLOR MENDEZ, KEVIN FLANNAGAN, DIANE SIMEONE, MARINA PASCA DI MAGLIANO. Myeloid cells are required to establish an immune-suppressive regulatory network in pancreatic cancer by activating the PD-1/PD-L1 checkpoint. [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 LB-205. doi:10.1158/1538-7445.AM2015-LB-205
Abstract LB-210: Telomerase activation by genomic rearrangements in high-risk neuroblastoma
Authors: Peifer Martin , Roels Frederik , Hertwig Falk , Menon Roopika , Kraemer Andrea , Buettner Reinhard , Perner Sven , Schramm Alexander , Schulte Johannes H. , Westermann Frank , Thomas Roman K. , Fischer Matthias 
Published: August 2015

Abstract
Neuroblastoma is a malignant pediatric tumor of the sympathetic nervous system. While roughly half of these tumors regress spontaneously or are cured by limited therapy, high-risk neuroblastomas have an unfavorable clinical course, despite intensive multimodal treatment. The genetic basis of the various clinical subtypes of the disease has remained largely elusive. To gain a better understanding of the genetic events that may drive neuroblastoma tumorigenesis, we here performed whole-genome sequencing of 42 primary neuroblastomas (high-risk, n = 25; low-risk, n = 17). We identified genomic rearrangements affecting chromosome 5p15.22 in a 50 kb region centromeric of the human telomerase reverse transcriptase gene (TERT) in 8 tumors. The rearrangements occurred only in high-risk neuroblastomas (8/25, 32%) in mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumor type. In an Independent validation cohort of 14 high-risk neuroblastomas, we detected rearrangements of the TERT locus in 4 additional samples. The structure of the rearrangements varied greatly, including balanced translocations, low-level copy number gains, focal amplifications and chromothripsis. Independent of the copy number at this region, all alterations consistently induced massive transcriptional up-regulation of TERT and of three additional genes located in close proximity to the chromosomal breakpoint. By contrast, MYCN-amplified tumors showed only up-regulation of TERT itself, suggesting that both MYCN amplification and TERT rearrangements converge on TERT activation. Supporting a functional role of TERT, both MYCN-amplified neuroblastoma cell lines and cell lines bearing TERT rearrangements exhibited elevated TERT expression and enzymatic telomerase activity in comparison to cell lines without these aberrations. Our findings show that remodeling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma, and places telomerase activation in the center of transformation in a large fraction of these tumors. More broadly, our findings provide a mechanistic basis for molecular diagnosis and therapy of this deadly pediatric tumor entity.
Citation Format: Martin Peifer, Frederik Roels, Falk Hertwig, Roopika Menon, Andrea Kraemer, Reinhard Buettner, Sven Perner, Alexander Schramm, Johannes H. Schulte, Frank Westermann, Roman K. Thomas, Matthias Fischer. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. [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 LB-210. doi:10.1158/1538-7445.AM2015-LB-210
Abstract LB-219: Interleukin-8 promotes generation of M2 macrophages and arginase-producing granulocytes: Prognostic significance of interleukin-8 and infiltration of immune cells positive for CD163 and CD66b in tumor tissues in patients with oral squamous cell carcinoma
Authors: Okamoto Masato , Fujita Yohei , Goda Hiroyuki , Nakashiro Koh-ichi , Hamakawa Hiroyuki 
Published: August 2015

Abstract
Biomarkers are essential for improving the effectiveness of treatments for patients with cancer. The immunological status in a tumor microenvironment is closely associated with the prognosis of cancer patients. Here we investigated whether serum interleukin (IL)-8 reflects the tumor microenvironment and has prognostic value in 50 patients with resectable oral squamous cell carcinoma (OSCC). We found that the relapse-free survival (RFS) was significantly longer in the Stage I/II OSCC patients with low serum IL-8 levels compared to those with high levels (p = 0.001). The tumor expression of IL-8, the infiltration of CD163-positive cells, and of CD66b-positive cells in the tumor tissues were correlated with the serum IL-8 level (p = 0.033, p = 0.038 and p = 0.044, respectively), and they were associated with poor clinical outcome (p = 0.007, p = 0.002 and p = 0.001 respectively, in DFS) in all patients. A multivariate analysis revealed that N status, tumor IL-8 expression, CD163 and CD66b infiltration significantly affected the DFS of the patients. A further analysis suggested that the combination of N status with serum IL-8, tumor IL-8, CD163 and CD66b infiltration in the tumor tissues may be a new criterion for discriminating between OSCC patients at high and low risk for tumor relapse. Finally, the in vitro experiments clearly demonstrated that IL-8 enhanced the generation of CD163-positive M2 macrophages from peripheral blood monocytes, and that the cells produced IL-10 which suppress anti-tumor immunity. Furthermore, IL-8 increased the generation of arginase-producing, CD66b-overexpressing cells from peripheral blood polymorphonuclear cells. These findings indicate that IL-8 may be involved in poor clinical outcomes via the generation of CD163-positive M2 macrophages and CD66b-overexpressing, arginase-producing granulocytes, and that these factors may have prognostic value as well as may be new targets for treatment in patients with resectable OSCC.
Citation Format: Masato Okamoto, Yohei Fujita, Hiroyuki Goda, Koh-ichi Nakashiro, Hiroyuki Hamakawa. Interleukin-8 promotes generation of M2 macrophages and arginase-producing granulocytes: Prognostic significance of interleukin-8 and infiltration of immune cells positive for CD163 and CD66b in tumor tissues in patients with oral squamous cell carcinoma. [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 LB-219. doi:10.1158/1538-7445.AM2015-LB-219
Abstract LB-240: SMARCE1 suppresses EGFR expression and controls responses to MET and ALK inhibitors in lung cancer
Authors: Papadakis* Andreas , Sun* Chong , Knijnenburg Theo , Xue Yibo , Grernrum Wipawadee , Hölzel Michael , Nijkamp Wouter , Wessels Lodewyk , Beijersbergen Roderick , Bernards# Rene , Huang# Sidong 
Published: August 2015

Abstract
Recurrent inactivating mutations in components of SWI/SNF chromatin-remodelling complexes have been identified across cancer types, supporting their roles as tumour suppressors in modulating oncogenic signalling pathways. We report here that SMARCE1 loss induces EGFR expression and confers resistance to MET and ALK inhibitors in non-small cell lung cancers (NSCLCs). We found that SMARCE1 binds to regulatory regions of the EGFR locus and suppresses EGFR transcription in part through regulating expression of Polycomb Repressive Complex component CBX2. Addition of the EGFR inhibitor gefitinib restores the sensitivity of SMARCE1 knockdown cells to MET and ALK inhibitors in NSCLCs. Our findings link SMARCE1 to EGFR oncogenic signalling and suggest targeted treatment options for SMARCE1 deficient tumours.
ACKNOWLEDGEMENTS: *Equal contribution. #Corresponding authors. This work was supported by grants from Canadian Institutes of Health Research (CIHR) grant MOP-130540 (S.H.), Canada Research Chair (CRC), the European Research Council (ERC), the Dutch Cancer Society (KWF), the EU COLTHERES project and grants by the Netherlands Organization for Scientific Research (NWO) to the Cancer Genomics Center Netherlands (CGC.NL).
Citation Format: Andreas Papadakis*, Chong Sun*, Theo Knijnenburg, Yibo Xue, Wipawadee Grernrum, Michael Hölzel, Wouter Nijkamp, Lodewyk Wessels, Roderick Beijersbergen, Rene Bernards#, Sidong Huang#. SMARCE1 suppresses EGFR expression and controls responses to MET and ALK inhibitors in lung 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 LB-240. doi:10.1158/1538-7445.AM2015-LB-240
Abstract LB-270: Screening of novel phytochemical/s that can protect breast epithelial cells from PhIP induced cytotoxicity
Authors: Jain Ashok K. 
Published: August 2015

Abstract
Amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP) is a known food carcinogen abundantly found in cooked meat. Several studies have shown that PhIP can induce tumors in breast, prostate and colon cells and rodent models. Metabolism of PhIP results in the formation of free radicals (ROS) and PhIP metabolites are known to produce DNA adduct and DNA strand breaks. The metabolism and mutational effects of PhIP are well defined. Phytochemicals are known to inhibit cytotoxic and genotoxic effects. Therefore, we hypothesized that the right combination of antioxidants and or phytochemical (naturally present in fruits, vegetables and spices) along with grilled meat should be capable of suppressing the PhIP induced cytotoxicity and development of breast cancer. Therefore, a model system using human breast epithelial cells (MCF 10A) was developed to mimic the cellular changes and test various antioxidants in presence or absence of PhIP. We have tested four vitamins (C, K3, D3, and E), Gingerol (6 and 10), N-acetyl cysteine, glutathione and curcumin at varying concentrations. The protective effect of these compounds was evaluated using cell viability assay, DCF assay to quantify ROS production, Comet assay to quantify the DNA damage and DNA adduct formation by immunofluorescence method. Results indicate that presence of these compounds improves cell viability as compared to PhIP treated group. However, curcumin showed significant differences and PhIP induced cell cytotoxicity was consistently reverted to normal in presence of Curcumin. Gene expression analysis using RT PCR technique indicates that curcumin interact via multi molecular targets. Hence, the present study suggests that Curcumin is a promising natural compound to regress the effect of PhIP induced cell cytotoxicity in breast cells.
Citation Format: Ashok K. Jain. Screening of novel phytochemical/s that can protect breast epithelial cells from PhIP induced cytotoxicity. [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 LB-270. doi:10.1158/1538-7445.AM2015-LB-270