bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 412: Role of Interferon Regulatory Factor (IRF)-3 in lung tumor microenvironment
Authors: Shirota Hidekazu , Klinman Dennis M. 
Published: August 2014

Abstract
Cytokines present in the tumor microenvironment influence whether a cancer progresses or is rejected. For example, IFNs promote anti-tumor immunity and thus contribute to tumor rejection whereas IL-10 and TGFb can inhibit anti-tumor immunity and thereby contribute to tumor survival. We find that IFNbeta levels are significantly up-regulated in the microenvironment surrounding lung tumors. In the B16 F10 mouse melanoma lung metastasis model, CD11c+ alveolar cells respond to tumor challenge by rapidly up-regulating their expression of IFNbeta. This induction of IFNbeta was totally absent in IRF3 KO mice but intact in MyD88 and TRIF KO mice. Challenge studies indicate that IRF3 KO mice develop more lung metastasis and have shorter survival than controls. These findings suggest that CD11c+ cells play an important role in tumor recognition, and that they mount an IRF3/IFNbeta pathway specific response that slows tumor progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 412. doi:10.1158/1538-7445.AM2011-412
Abstract 4122: Multi-center validation of a lymph node metastasis gene-expression signature for head and neck squamous cell carcinomas
Authors: Speel Ernst-Jan M. , Leusink Frank K.J. , van Hooff Sander R. , Kummer J Alain , van Diest Paul J. , Koole Ronald , Roepman Paul , van den Brekel Michiel W.M. , Merkx Thijs A. , Jansen Jeroen C. , Schuuring Ed M.D. , Brakenhoff Ruud H. , Baatenburg de Jong Robert J. , Slootweg Piet J. , Holstege Frank C.P. , Takes Robert P. 
Published: August 2014

Abstract
Background: The inability of current diagnostic tools to detect small lymph node metastases in patients with Head and Neck Squamous Cell Carcinoma (HNSCC) leads to a rate of undetected metastases that is too high to refrain from elective neck treatment, resulting in overtreatment. The aim of this study is validation of a gene expression signature for distinguishing metastasizing from non-metastasizing HNSCC on a large multi-center cohort.
Material and methods: Samples of oral cavity and oropharyngeal cancer were collected from all head and neck oncological centers in the Netherlands. Gene expression was analyzed with a DNA microarray representing 696 previously reported predictive genes. The negative predictive value (NPV) was assessed on the whole cohort (n=222), on a subset including only clinically node negative (cN0) tumors (n=143) and on the most relevant subset that included T1 and T2, cN0 oral cavity tumors (n=101). Histological examination was used as gold standard for nodal status.
Results: Overall, the NPV of the signature was 72 %. The signature performed better on the cN0 subset (NPV 85%) and very well in the clinically most relevant subset of T1 and T2, cN0, oral cavity SCC (NPV 89%).
Conclusion: Combining the results of clinical and radiological examination with the gene expression signature decreases the rate of undetected nodal metastasis to 11 % in the relevant group of early stage cancers of the oral cavity. This result should be considered sufficient to refrain from elective neck treatment in these patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4122. doi:10.1158/1538-7445.AM2011-4122
Abstract 4132: Predictive classifiers for response to c-Met targeted therapies in lung and colon cancer
Authors: Drubin David , Catlett Natalie L. , Park Jennifer , Van Hooser Aaron A. , Frushour Brian P. , Kenney Renee Deehan 
Published: August 2014

Abstract
A fundamental challenge in the development of cancer therapies is the co-development of companion biomarkers to select patients most likely to respond to treatment prior to the availability of clinical outcomes data. We developed a methodology that leverages large scale public ‘omics data to identify candidate predictive biomarker panels to identify patients with a greater likelihood of responding to targeted therapies. We applied this approach to generate mechanism-based predictive biomarkers using our causal Knowledgebase as a substrate, as well as standard gene expression-based biomarkers for c-Met targeted therapy use in lung and colon cancers, and validated the methodology using clinical data. Gene signatures for c-Met activation in lung and colon were applied to individual lung and colon cancer training set patients to stratify them by c-Met activation levels. Data from patients identified as having high and low levels of c-Met activation were used to develop mechanism-based and gene expression-based classifiers to predict response to c-Met targeted therapies in lung and colon cancer. Validation of these classifiers requires transcriptomic data with associated clinical outcomes from c-Met inhibitor trials. In the absence of such, we verified this general approach using data from Inflammatory Bowel Disease (IBD) patients treated with the TNF inhibitor Infliximab, for which published colon transcriptomic data and associated clinical outcomes data are available {GSE16879} We developed a gene signature to assess TNF pathway activation and stratify a training set of IBD patients, then generated gene expression and mechanism-based classifiers from patients with high and low TNF signaling. These classifiers were tested on an independent test set of IBD patients treated with Infliximab {GSE12251}; the mechanism and gene expression-based classifiers predicted responders with positive and negative predictive values of 85%/88% and 70%/100% respectively. This method can be applied to other targets, pathways and diseases and may facilitate companion diagnostic development by enabling the selection of appropriate patient populations prior to treatment and clinical trial participation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4132. doi:10.1158/1538-7445.AM2011-4132
Abstract 4133: Is mitochondrial DNA copy number associated with interval colorectal cancers
Authors: Thyagarajan Bharat , Barcelo Helene , Shaukat Aasma 
Published: August 2014

Abstract
Colorectal cancers diagnosed in the interval after a complete colonoscopy (interval colorectal cancers) may occur due to due to rapid tumor growth. We have previously demonstrated that microsatellite instability (MSI) is associated with interval colorectal cancers. Mitochondrial DNA copy number has been shown to be inversely associated with rapid tumor growth in lung and breast cancers. However, the association of mitochondrial DNA copy number with interval colorectal cancers, MSI and survival remains unknown. The aim of our study was to study the association of mitochondrial DNA copy number with interval colorectal cancers, MSI and 5-year survival. We conducted a case-control study of 63 interval and 131 frequency matched non-interval colorectal cancers at the Veterans Administration Medical Center. Interval colorectal cancers were defined as colorectal cancers that developed within 5 years of a complete colonoscopy. Archived tumor specimens were tested for mitochondrial DNA copy number and MSI status. Relative mitochondrial DNA copy number was measured by a quantitative real-time polymerase chain reaction (PCR) assay using two pairs of primers, one specific for amplification of the mitochondria- specific gene (ND1) and another specific for amplification of a nuclear gene (CD3). Multivariable logistic regression was used to evaluate the association between mitochondrial DNA copy number, MSI and interval colorectal cancers. Cox proportional hazards regression was used to evaluate the association between mitochondrial DNA copy number and survival. Median mitochondrial copy number was 5.11 (range 1.4-193). Assay reproducibility, based on 20 samples run in duplicate, was 11%. There was no association between mitochondrial DNA copy number and interval colorectal cancers (OR 0.9; 95% CI 0.66-1.22; p 0.50), but mitochondrial DNA copy number was inversely associated with MSI status (OR 0.32; 95% CI 0.18-0.55; p &lt;.001). There was a trend towards lower overall 5-year survival with lower copy number (HR 0.89; 95% CI 0.74-1.08; p 0.07), and a significantly lower survival with lower copy number among stage IV colorectal cancers (HR 0.53; 95% CI 0.31-0.90; p 0.02). Mitochondrial DNA copy number is inversely associated with MSI and overall survival for colorectal cancer. Low mitochondrial DNA copy number may be a marker of rapid tumor growth and poor survival in colorectal cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4133. doi:10.1158/1538-7445.AM2011-4133
Abstract 414: Does hedgehog signaling activation affect the tumor immune suppression microenvironment
Authors: Yang Ling , Gu Dongsheng , Liu Hailan , Zhang Xiaoli , Xie Jingwu 
Published: August 2014

Abstract
As an important pathway in embryonic development, hedgehog signaling plays a major role in stem cell maintenance, cell differentiation, tissue differentiation and tissue remodeling. Amounting evidence indicate that hedgehog signaling is frequently activated in a variety of human cancer. In consistent with the stromal effect of hedgehog signaling in development, several recent studies indicate a role of hedgehog signaling in tumor-stromal interaction. The molecular mechanisms by which hedgehog signaling regulates tumor microenvironment, however, remain largely elusive. We have generated data to support that hedgehog signaling regulates tumor immune surveillance. In a mouse model of hedgehog-mediated carcinogenesis, we found that activation of hedgehog signaling is associated with an increase in myeloid-derived suppressor cell (MDSC) population, which is decreased after hedgehog signaling inhibition. Our Based on our data, it is proposed that hedgehog signaling creates an immune suppressive environment through regulation of MDSC population, which is in concert with hedgehog signaling- mediated cell proliferation to promote carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 414. doi:10.1158/1538-7445.AM2011-414
Abstract 4144: Identification of molecules involved in PpIX accumulation in brain tumor induced by oral administration of 5-ALA
Authors: Suzuki Tomonari , Wada Satoru , Eguchi Hidetaka , Wakiya Kenji , Adachi Junichi , Mishima Kazuhiko , Nishikawa Ryo , Nishiyama Masahiko 
Published: August 2014

Abstract
[Background and Purpose] 5-aminolevulinic acid (5-ALA) is one of leading compounds widely used in photodynamic diagnosis and therapy of solid tumors: 5-ALA is metabolically converted to protoporphyrin IX (PpIX), a fluorescent molecule in response to excitation with a laser beam of 405 nm wavelength, that accumulates specifically in tumor lesions. This is found to be very effective for intra-operative detection of malignant brain tumors such as glioblastoma multiforme (GBM). On the other hand, we occasionally encountered cancerous lesions that are apparently malignant under a white light, while showing no fluorescence of the PpIX during cyto-reductive operation of the GBM. In order to overcome this problem, we hereby searched for factors associated with either presence or absence of the PpIX fluorescence by means of comprehensive gene expression analysis.
[Materials and Methods] Thirty-one patients of brain tumor (21 GBM, 3 pilocytic astrocytoma and 7 oligodendroglial tumors), orally-administrated with 5-ALA followed by operation under a fluorescence-guide, were enrolled in this study. Tumor specimens with or without the 5-ALA induced-fluorescence were collected from these patients and snap-frozen in liquid nitrogen. Total RNAs were extracted from the frozen tissues and were subjected to a comprehensive gene expression analysis using Whole Human Genome 4×44K Oligo Microarray (Agilent). We then compared gene expression levels between specimens with or without the fluorescence among individuals and selected candidate genes of which gene expression levels significantly differ between these. For validation, quantitative gene expression analyses were conducted for the candidates with real-time RT-PCR using gene specific-primers and probes. Knockdown experiments using specific siRNAs were also performed in cell lines derived from GBM to test their biological significance.
[Results and Discussion] A total of 14 genes were initially selected as candidates that were associated with PpIX accumulation in GBM in the microarray analysis. Among these, CDH13 (cadherin 13) gene was expressed significantly higher in the fluorescence-positive GBMs than in negative ones. Knockdown of CDH13 gene expression in GBM cells treated with 5-ALA, attenuated the fluorescence intensity, indicating its possible role in PpIX accumulation. Further experiments are underway to elucidate molecular mechanisms of CDH13 in 5-ALA-induced PpIX fluorescence in brain tumor.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4144. doi:10.1158/1538-7445.AM2011-4144
Abstract 4151: High definition circulating tumor cells in patients with non-small cell lung cancer
Authors: Wendel Marco , Bazhenova Lyudmila , Nieva Jorge , Bethel Kelly , Marrinucci Dena , Cho Edward H. , Yoshioka Craig , Luttgen Madelyn , Uson Loressa , Metzner Thomas , Kolatkar Anand , Torrey Melissa , Kuhn Peter 
Published: August 2014

Abstract
Circulating tumor cell (CTC) counts are an established prognostic marker in metastatic prostate, breast, and colorectal cancer. However, there is little knowledge about CTC incidence rates and morphologic heterogeneity in non-small cell lung cancer (NSCLC) and their correlation to disease progression and usability for clinical staging. Here, we present a fluid phase biopsy approach that identifies CTCs without surface receptor-based enrichment, and presents them in sufficiently high definition (HD) to satisfy diagnostic pathology image quality requirements. The HD-CTC assay will be used to monitor HD-CTC counts and morphology in early stage, locally advanced, and metastatic NSCLC patient over time. 150 newly diagnosed NSCLC patients are being enrolled for this project. At the time of diagnosis 50 of the patients will have early stage cancers (stage I-II); 50 patients will have locally advanced (stage III) cancers, and 50 will be patients presenting with metastatic (stage IV) disease. Blood samples from each patient will be obtained at the time of diagnosis and 6 months later. We present here an interim data set that shows an incidence rate of 78% at baseline with a median CTC count of 19.5/ml of blood (range 0-441.6). Our preliminary data demonstrates that, despite stringent morphologic inclusion criteria for the definition of HD-CTCs, our HD-CTC assay shows high sensitivity in the detection of lung cancer CTCs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4151. doi:10.1158/1538-7445.AM2011-4151
Abstract 4154: Multi-parameter molecular characterization of circulating tumor cells (CTC): Development of a CTC-endocrine therapy index (CTC-ETI)
Authors: Paoletti Costanza , Brown Martha , Muñiz Maria , Rae James M. , Thomas Dafydd G. , Hayes Daniel F. 
Published: August 2014

Abstract
Introduction. CTC can be reproducibly and reliably enumerated using a commercially-available, automated immunomagnetic system (CellSearch®; Veridex LLC). High levels of CTC predict rapid progression in patients with metastatic breast cancer (MBC). Only ∼ 50% of patients with estrogen receptor (ER) positive MBC benefit from endocrine therapy (ET). Patients with endocrine-refractory MBC are better palliated with chemotherapy. We have developed a multi-parameter assay using CellSearch® that may identify patients with ER positive MBC who are unlikely to benefit from ET and may be better served with chemotherapy.
Methods. CellSearch® has four fluorescence channels. Three of these are used to distinguish CTC from WBC (DAPI, anti-cytokeratin, anti-CD45). The 4th “empty” channel was used to measure ER, Bcl-2, HER2, and Ki67 expression with antigen-specific fluorescent-labeled antibodies. These four markers were chosen because of their associations with sensitivity (ER, Bcl-2) or resistance (HER2, Ki-67) to ET. Cultured human breast cancer cells (MCF-7: ER +, BCL-2 +, HER2 -, Ki67 +; MDA-MB-231: ER -, Bcl-2 -, HER2 -, Ki67 +; BT-474: ER +, Bcl-2 +, HER2 +, Ki67 +) were spiked into 7.5 ml human whole blood from normal donors and separated and characterized using the CXC CellSearch® kit.
Results. Each cell line stained appropriately for the respective markers, with appropriate negative controls, although staining was heterogeneous, even within a single cell line. Using these preliminary data, we have developed a CTC-ETI in which scores are assigned to the individual categories consisting of cell counts coupled with the relative percent and degree of cell positivity of each marker. We predict that lower scores (low or no CTC, or CTC with high % and intensity of ER and Bcl-2; low HER2 and Ki-67) will be associated with favorable response to ET.
Conclusions. CellSearch® can be used to measure the expression of 4 clinically useful and proven breast cancer biomarkers. A clinical trial is underway at U. Michigan to permit calculation of CTC-ETI in patients with MBC, which will lead to a prospective trial to determine if high CTC-ETI predicts resistance and rapid progression on ET.
Supported by Veridex, LLC, Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale ™ (DFH), Associazione Sandro Pitigliani and by a studentship from FIRC (CP)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4154. doi:10.1158/1538-7445.AM2011-4154
Abstract 4155: Simultaneous quantitation of multiple signaling molecules in individual circulating tumor cells (CTCs) by multi-color laser scanning cytometry
Authors: Wu Weiguo , Zhang Yujian , Neil Chris , Copper Geoffrey M. , Kahn Larry , Melnikova Vladislava , Woo Jacky , Davis Darren 
Published: August 2014

Abstract
Introduction: Recent advances in circulating tumor cell (CTC) technology provide a new alternative approach to examine proteomic and molecular characteristic of tumor cells from cancer patients. The current trend in anti-cancer drug development focuses on new compounds that modulate multiple signaling pathways. With CTC detection used as a potential liquid biopsy, the simultaneous examination of signaling molecules for multiple pathways on the same CTC could provide insight into the drug activity in tumor cells. We used proprietary laser scanner cytometry (LSC) technology and developed a multi-color immunofluorescence (IF) procedure to detect 7 biomarkers within the same CTC. We validated this new staining technology using the (1) receptor tyrosine kinase pathways based molecules included total and phospho-IGF-1R, in combination with total and phospho-EGFR, or with total and phospho-ERK1/2, or with total and phospho-AKT (S473) in HT-29 colorectal tumor cells, and (2) same marker expression in CTCs enriched from cancer patients. Purpose: To validate the new multiple marker IF staining procedure and laser scanning cytometry (LSC) platform using ligand treated or untreated tumor cells, and in CTCs enriched from cancer patients. Method: A target biomarker staining panel was combined with standard CTC staining (DAPI, CK+ and CD45-) to create a 7-color IF staining panel to examine marker expression in tumor cell lines and in CTCs from cancer patients. Cultured tumor cells and CTCs enriched from Cellsearch Profile were cytospun onto slides, stained, scanned (by LSC) and analyzed. Results: Using a simultaneous co-staining procedure and LSC-based analysis, we demonstrated that treatment of HT29 cells with IGF1 for 15-30 minutes induced significant increases in both p-IGF1R expression and p-ERK1/2 and p-AKT expression on HT29 cells. In addition, anti-IGF1R and/or anti-EGFR, or with multi-kinase inhibitor treatment leads to differential reduction of p-ERK1/2 and p-AKT. Using CTCs enriched from cancer patient, simultaneous detection of multiple signaling molecules was also observed. Summary A multi-color, LSC-based methodology was developed to quantify expression of up to 4 biomarkers in CTCs. Application of this technology in clinical studies to examine the activation status of CTCs from patients could provide important information on pathway-specific drug activity and guide dosing selection.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4155. doi:10.1158/1538-7445.AM2011-4155