bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4272: Applying TCGA data for breast cancer diagnostics and pathway analysis
Authors: Andersen Jannik , Shah Parantu , Korski Konstanty , Ibbs Matthew , Filas Violetta , Kosiedowski Michal , Pukacki Juliusz , Mazurek Cezary , Wu Yuanqing , Chang Edward , Toniatti Carlo , Draetta Giulio , Wiznerowicz Maciej 
Published: May 2015

Abstract
The main objective of our project is to obtain a comprehensive insight into oncogenic signaling in order to develop novel diagnostic tools for molecular subtypes of breast cancer (BRCA). We have provided about 100 BRCA samples along with full pathology and clinical annotations to the TCGA program. These cancer samples have been extensively characterized using all available genomics platforms and the obtained molecular data contributed to the molecular characterization of BRCA. This integrated effort identified four major molecular subtypes of breast cancer that can be identified across five profiling platform including genomics, transcriptomics and proteomics (Nature, 490 (7418):61-70). Building upon these datasets we aim to translate these genomics profiles into diagnostic tools that can be used in every day medical practice. In the first step, we have generated tissue microarrays (TMAs) from FFPE BRCA samples obtained from the patients enrolled into the TCGA project. Next, the TMA slides were used for immunohistochemistry (IHC) using about 100 antibodies specific for major cancer markers, including oncogenic kinases frequently activated or overexpressed in BRCA. The obtained IHC results have been scored and verified independently for each marker by two board-certified pathologists. To identify markers that correlate with or are specific to the molecular subtypes of BRCA, the TMA/IHC read-outs from each tumor sample were correlated with all TCGA genomic data. In addition, we integrate the pathology and genomics results with clinical data obtained from the TCGA-enrolled patients, including up to 4 years follow-up. Finally, we apply system biology tools to integrate the genomic data from TCGA with the proteomic analysis to understand causalities between changes in DNA, transcriptome and signal transduction pathways. Our long-term goal is to identify novel diagnostic biomarkers that will precisely identify each molecular subtype of BRCA and which may be predictive of patient response to therapy thus paving the way for novel personalized therapies for cancer.
Citation Format: Jannik Andersen, Parantu Shah, Konstanty Korski, Matthew Ibbs, Violetta Filas, Michal Kosiedowski, Juliusz Pukacki, Cezary Mazurek, Yuanqing Wu, Edward Chang, Carlo Toniatti, Giulio Draetta, Maciej Wiznerowicz. Applying TCGA data for breast cancer diagnostics and pathway analysis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4272. doi:10.1158/1538-7445.AM2014-4272
Abstract 4279: Rapid biomarker discovery using large-scale, patient-derived cancer genomic cohorts
Authors: Sanga Sandeep , Nair Praveen , Mirsaidi Cyrus , Broudy Thomas 
Published: May 2015

Abstract
Target discovery and validation in oncology has largely relied on molecular and functional studies performed in cell lines. Recent advances in genomics have now created large databases based on well-characterized tumor tissue, which has enabled direct investigation of patient tumors for novel targets and predictive markers. Following these discoveries, it is routine to perform functional studies in cell line-based systems; however, it is often challenging to find a relevant cell line model and if found, there are often numerous factors which confound biology when using historical cell lines for functional studies. The result can be a process, which takes considerable time and does not readily translate to clinical relevance.
We report here our efforts to identify novel targets and markers through data mining large cohorts of cancer genomics data consisting of samples deriving from both drug-naïve and -treated patient-derived cancer samples. To serve as the drug-naïve reference, we look to the thousands of patient-derived tumor specimens, covering 30+ tissue types, genomically characterized by The Cancer Genome Atlas. For both drug-naïve and drug-treated primary data, we leverage Molecular Response's proprietary bank of viable cryopreserved tumor cells. The bank contains more than 144,000 tumor specimens, covering 25 tissue types and 76 clinical diagnoses. Each of the specimens has been profiled against a panel of drugs ex vivo, and levels of resistance recorded. Nearly 400 tumor specimens from Molecular Response's proprietary bank have been genomically characterized.
Station X has designed and developed a software environment called GenePool for the management, analysis and communication of genomic information for cohort-scale biomarker studies. The genomics data along with sample-associated clinical metadata deriving from Molecular Response's bank and The Cancer Genome Atlas were imported into GenePool. We evaluated consistency between drug-naïve samples deriving from the Molecular Response bank and TCGA, and subsequently mined for expression-based markers differentiating varying grades of drug sensitivities from drug-naïve specimens. We are currently evaluating these markers for further functional study in patient-derived models and plan to report to these findings.
Citation Format: Sandeep Sanga, Praveen Nair, Cyrus Mirsaidi, Thomas Broudy. Rapid biomarker discovery using large-scale, patient-derived cancer genomic cohorts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4279. doi:10.1158/1538-7445.AM2014-4279
Abstract 4286: Improved FFPE DNA extraction for next generation sequencing using adaptive focused acoustics technology
Authors: Lin Ling , Vega Mikenah , Jones Robert T. , Ziaugra Liuda , Dolcen Deniz N. , Sunkavalli Ashwini , Schubert Laura , Lepine Jack R. , Thorner Aaron R. , Ducar Matthew D. , Hahn William C. , Meyerson Matthew L. , MacConaill Laura E. , Hummelen Paul Van 
Published: May 2015

Abstract
Formalin fixation followed by paraffin embedding (FFPE) is the most widely used method of tissue preservation and often used in the clinical setting for cancer specimens. However, this process of fixation has negative consequences on the quality of extracted DNA, and inevitably adversely affects downstream analyses such as next generation sequencing (NGS). DNA extraction from FFPE samples requires paraffin disassociation, tissue rehydration and de-crosslinking. Low efficiency in any step will yield low quantities of nucleic acids with incomplete reversal of formaldehyde crosslinks, and mixtures of single and double stranded DNA. In addition, low quality nucleic acids will often result in poor sequencing quality due to inefficient library preparation, lower number of reads with high quality, and variable recovery of sequence reads with high GC-content.
Here we describe the use of Adaptive Focused Acoustics technology (Covaris Inc. 2013) to remove paraffin and break down tissue, and we compared this method to traditional xylene-based paraffin removal. We found that Covaris had superior performance overall: (1) DNA yields were 6 times higher, and less specimens failed extraction: this is critically important when dealing with small tumor biopsies. (2) DNA was more readily available for PCR amplification. (3) Mean coverage of DNA fragments with high GC content was higher and more reproducible. (4) Library complexity was higher. In addition, the Covaris protocol required less hands-on time in the lab, and eliminated the need for hazardous organic solvents for paraffin removal.
In conclusion, the Covaris FFPE DNA extraction method is very efficient, enhances DNA availability, improves reproducibility and provides higher DNA quality for NGS.
Citation Format: Ling Lin, Mikenah Vega, Robert T. Jones, Liuda Ziaugra, Deniz N. Dolcen, Ashwini Sunkavalli, Laura Schubert, Jack R. Lepine, Aaron R. Thorner, Matthew D. Ducar, William C. Hahn, Matthew L. Meyerson, Laura E. MacConaill, Paul Van Hummelen. Improved FFPE DNA extraction for next generation sequencing using adaptive focused acoustics technology. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4286. doi:10.1158/1538-7445.AM2014-4286
Abstract 43: Podoplanin in head and neck squamous cell carcinoma: Prognostic value and clinicopathological implications
Authors: Koo Bon Seok , Lim Kyu 
Published: May 2015

Abstract
Background: Podoplanin is a mucin-type transmembrane glycoprotein that is important in lymphangiogenesis. We investigated the associations of podoplanin expression status with clinicopathological variables and the prognostic influence of podoplanin expression in head and neck squamous cell carcinoma (HNSCC), to determine its effectiveness as a marker of high-risk HNSCC subjects.
Patients and Methods: We analyzed by immunohistochemistry podoplanin expression and its associations with the clinicopathological characteristics of 119 surgically treated HNSCC cases. Additionally, we investigated the effects of podoplanin expression on overall survival and disease-specific survival in univariate and multivariate analyses.
Results: Of 119 HNSCC patients, high podoplanin expression was found in 61 cases (51.3%) and low expression in 58 (48.7%). High podoplanin expression was associated with lymph node metastasis, advanced AJCC stage, and poor histological grade (p &lt; 0.05). In multivariate analysis, high podoplanin expression was significantly associated with circa three- and fivefold increases in the presence of positive lymph node metastasis and poor histological grade, respectively (p &lt; 0.05). High levels of podoplanin expression were significantly associated with decreased overall survival and disease-specific survival (p &lt; 0.05).
Conclusions: Our findings suggest that high podoplanin expression is associated with aggressive tumor behavior and poor prognosis in HNSCC.
Note: This abstract was not presented at the meeting.
Citation Format: Bon Seok Koo, Kyu Lim. Podoplanin in head and neck squamous cell carcinoma: Prognostic value and clinicopathological implications. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 43. doi:10.1158/1538-7445.AM2014-43
Abstract 430: Identification of novel methylation-silenced genes in oral squamous cell carcinomas
Authors: Abe Masanobu , Yamashita Satoshi , Mori Yoshiyuki , Abe Takahiro , Saijo Hideto , Ushijima Toshikazu , Takato Tsuyoshi 
Published: May 2015

Abstract
To identify novel methylation-silenced genes in oral squamous cell carcinomas (OSCCs), we took a combined approach of methylated DNA immunoprecipitation (MeDIP)-CpG island (CGI) microarray analysis and expression microarray analysis after treatment with a demethylating agent. MeDIP-CGI microarray revealed that promoter CGIs of 324 genes were methylated in two OSCC cell lines (Ca9-22, HSC-2). By treatment of the cell lines with 5-aza-2′-deoxycytidine, 125 of the 324 genes were up-regulated in at least one of the two cell lines. For 23 of the 125 genes that have not been focused on in the field of oral malignancy, we analyzed their promoter methylation statuses in 16 normal oral tissues, five OSCC cell lines, 26 OSCC tissues and 24 oral leukoplakia tissues. Ten promoter CGIs were methylated not only in OSCC cell lines but also OSCC tissues. The methylation profile indicated the presence of the CpG island methylator phenotype (CIMP) in OSCC tissues. Furthermore, the CIMP was observed in three of the 13 oral dysplastic leukoplakia tissues. The CIMP was considered as one of early molecular events in malignant transformation from oral premalignant lesions to OSCCs.
Citation Format: Masanobu Abe, Satoshi Yamashita, Yoshiyuki Mori, Takahiro Abe, Hideto Saijo, Toshikazu Ushijima, Tsuyoshi Takato. Identification of novel methylation-silenced genes in oral squamous cell carcinomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 430. doi:10.1158/1538-7445.AM2014-430
Abstract 4305: Biodistribution and clearance of non-targeted DyLight dyes in tumor-free nude mice for in vivo imaging
Authors: NLEND Marie C. , Desai Surbhi , Hong Suk J. , Anderson Mary Beth , Los Georgyi V. , Hermanson Greg T. , Diener Justin M. , Leevy Warren M. , Bell Peter A. 
Published: May 2015

Abstract
Far red to near infra red (NIR) fluorophores are commonly used in cell-based assays and for deep tissue in vivo imaging. The light emitting and physico-chemical characteristics of these fluorophores, e.g. excitation and emission spectra, relative hydrophilicity/hydrophobicity and molecule size, can significantly influence their performance in these applications. Currently there are no guidelines for selection of fluorophores optimal for targeted in vivo imaging. To address this issue we have designed a panel of DyLight dyes with maximum excitation wavelength in the range of 650 -785 nm, maximum emission wavelength in the range of 670 - 800 nm and different levels of sulfonation and/or PEGylation. We studied the kinetic of tissue distribution and clearance of these fluorophores as well as their effect on morphology of different tissues in mice after intravenous injection. Briefly, nude mice were anesthetized, injected with a dye (100 µL of dye at 0.5mg/ml in PBS) into retro-orbital plexus, and imaged using Carestream MSFX or Carestream XTREME Imager. Images were generated before dye injection, immediately after injection (0 hours) and 3, 6, 12 and 24 hours post injection. At the end of the experiment, animals were sacrificed; internal organs were collected and used for ex vivo analysis. The results of in vivo imaging experiments demonstrated that: hydrophobic fluorophores have a relatively slow kinetic of distribution and clearance, and often cleared via a hepatic pathway. Introduction of the negatively charged groups and or PEG chains increased dye solubility affected the kinetics of both fluorophore distribution and its clearance. In addition, negatively charged fluorophores had a tendency to be cleared predominantly via renal pathway. A histological analysis of the internal organs showed no detectable tissue damage. These results provide guidelines for the selection of optimal NIR dyes for in vivo imaging.
Citation Format: Marie C. NLEND, Surbhi Desai, Suk J. Hong, Mary Beth Anderson, Georgyi V. Los, Greg T. Hermanson, Justin M. Diener, Warren M. Leevy, Peter A. Bell. Biodistribution and clearance of non-targeted DyLight dyes in tumor-free nude mice for in vivo imaging. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4305. doi:10.1158/1538-7445.AM2014-4305
Abstract 4306: Bioconjugation of near infrared dyes by PEGylation improves pharmacokinetics and allows for better labeling and imaging of human gastrointestinal cancers
Authors: Maawy Ali A. , Hiroshima Yukihiko , Luiken George A. , Zhang Yong , Hoffman Robert M. , Bouvet Michael 
Published: May 2015

Abstract
NIR dyes are becoming increasingly popular due to their good tissue penetration, low tissue autofluorescence and resistance to hemoglobin quenching. However, they are still limited by lower hydrophilicity and poor chemical and photo-stability in-vivo. We aimed to try to improve these properties by covalent modification of these dyes by addition of polyethylene glycol (PEG) chains. We studied 2 commercially-available NIR dyes, DyLight 650 and 750, to evaluate how PEGylation affects the pharmacokinetics, biodistribution and imaging. PEGylated and non-PEGylated DyLight 650 and 750 dyes were conjugated to a chimeric anti-CEA antibody and were injected intravenously into nude mice. Serum samples were collected at various time points to determine serum concentrations and clearance kinetics. Biodistribution was determined by tissue sonication and analyzing tissue concentration profiles over time. PEGylated dyes had significantly higher serum concentrations than non-PEGylated dyes with p=0.005 for the 650 dyes and p&lt;0.001 for the 750 dyes. PEGylated dyes had significantly lower liver concentrations (p=0.03 for the 650 dyes; p=0.002 for the 750 dyes) and higher renal concentrations (p=0.003 for the 650 dyes and p&lt;0.001 for the 750 dyes) compared to non-PEGylated dyes. Human pancreatic tumors subcutaneously implanted into nude mice were labeled with antibody-dye conjugates and serially imaged. Labeling with PEGylated dyes resulted in significantly brighter tumors compared to the non-PEGylated dyes (p&lt;0.001 for the 650 dyes; p=0.01 for 750 dyes). In a liver metastasis model of colon cancer, PEGylated dyes showed bright labeling of metastatic tissue with good contrast between normal and malignant tissue. PEGylation of the NIR dyes DyLight 650 and 750 significantly changes their pharmacokinetics and biodistribution, allowing higher serum concentrations, longer half-life, brighter tissue labeling and decreased accumulation in lymphoid organs. This allows for high fidelity imaging of metastatic disease to any lymphoid or hemoglobin dense organ such as the liver.
Citation Format: Ali A. Maawy, Yukihiko Hiroshima, George A. Luiken, Yong Zhang, Robert M. Hoffman, Michael Bouvet. Bioconjugation of near infrared dyes by PEGylation improves pharmacokinetics and allows for better labeling and imaging of human gastrointestinal cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4306. doi:10.1158/1538-7445.AM2014-4306
Abstract 4314: Metabolic manipulation of hypoxia and radiotherapy response by electron transport inhibitors
Authors: Gandolfo Maria Jose , Kyle Alastair H. , Minchinton Andrew I. 
Published: May 2015

Abstract
The presence of hypoxia in solid tumors is correlated with poor treatment outcome. Even small population of hypoxic cells within tumors can significantly decrease the efficacy of radiation therapy. One approach to treating hypoxia in tumours is to reduce overall tumor cell oxygen consumption by modulating mitochondrial respiration. This could reoxygenate hypoxic cells within the tumor and restore radiation sensitivity. To guide in vivo application we tested the effects of three respiratory chain inhibitors; the biguanides metformin and phenformin and rotenone on oxygen consumption in 3D tissue engineered discs.
Experiments were carried out to evaluate the effect of respiratory inhibition on the hypoxic fraction of HCT116 and HT29 tissue discs using immunostaining with the hypoxic cell marker pimonidazole. An oxygen sensing phosphorescence lifetime probe assessed pO2 on the basal side of the disc as a function of time after inhibitors were exposed to the apical surface. Clonogenic assays were then performed to confirm the radiosensitization of hypoxic cells within the tissue discs.
Pimonidazole staining and direct pO2 sensing confirmed that all three electron transfer inhibitors decrease the hypoxic fraction by reducing cellular oxygen consumption. Rotenone was found to completely eliminate the hypoxic fraction at nanomolar concentrations compared to metformin and phenformin which require milli to micromolar concentrations respectively. Furthermore, rotenone was found to have an effect on oxygen utilization within minutes of drug exposure compared to both metformin and phenformin, which took hours to be effective. In addition, clonogenics assays determined that all three electron transfer inhibitors radiosensitize tumor cells with rotenone being the most efficient compound on a molar basis.
The mitochondrial inhibitors of complex I metformin, phenformin and rotenone decrease oxygen utilization by tumor cells in a concentration dependent manner resulting in reduction of the hypoxic fraction and increased radiosensitivity.
Citation Format: Maria Jose Gandolfo, Alastair H. Kyle, Andrew I. Minchinton. Metabolic manipulation of hypoxia and radiotherapy response by electron transport inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4314. doi:10.1158/1538-7445.AM2014-4314
Abstract 4316: BNIP3 suppresses mammary tumorigenesis and metastasis through negative regulation of Warburg effect and HIF-1α
Authors: Chourasia Aparajita Hoskote , Tracy Kristin , Boland Michelle , Sharifi Marina , Macleod Kay F. 
Published: May 2015

Abstract
BNIP3 is a hypoxia-inducible protein involved in mitochondrial dynamics and mitophagy that is up-regulated at pre-malignant stages of various human cancers, including breast cancer but down-regulated at later stages of tumorigenesis. To examine the role of BNip3 in tumor progression, we crossed BNip3 null mice to the MMTV-PyMT mouse model of breast cancer. Loss of BNip3 promoted primary tumor growth in vivo and tumor cell proliferation in vitro and was associated with increased aerobic glycolysis and reduced mitochondrial respiration. BNip3 null tumor cells also showed increased invasive properties that were cell intrinsic and transplantable to wild-type host mice. Consistently, there was reduced latency to lung metastasis in the MMTV-PyMT;BNip3-/- mice and increased numbers of metastases compared to control mice. BNip3 null tumors exhibited increased mitochondrial mass, but a greater fraction of mitochondria were dysfunctional with reduced membrane potential and decreased metabolite uptake compared to BNip3 wild-type tumor cells. Consistently, increased proliferation of BNip3 null tumor cells was associated with increased carbon flux from glucose to lipid and nucleic acids. Interestingly, although mitochondria were less efficient at uptake of pyruvate and glutamine, the rate of production of Krebs cycle intermediates was increased. This indicates that defective mitochondria due to inefficient mitophagy can induce the Warburg effect, as originally proposed by Warburg himself. Loss of BNip3 also resulted in more hypoxic tumors that expressed increased levels of Hif-1α and its target genes and showed increased angiogenesis, although blood vessels were abnormal possibly explaining increased tumor hypoxia, thus suggesting a negative feedback loop between Hif-1α and its target gene, BNip3. Inhibition of glycolysis or inhibition of HIF activity reduced proliferation in BNip3 null tumor cells to the levels observed in control cells. Significantly, BNip3 null tumor cells underwent autophagic flux as efficiently as wild-type cells demonstrating for the first time that inhibition of mitophagy has a distinct tumorigenic consequence to general inactivation of autophagy, as reported elsewhere. These results demonstrate that BNip3 has tumor and metastasis suppressor properties required to maintain mitochondrial integrity, promote oxidative metabolism and mitigate against the metastasis promoting activities of hypoxia and glycolytic metabolism.
Citation Format: Aparajita Hoskote Chourasia, Kristin Tracy, Michelle Boland, Marina Sharifi, Kay F. Macleod. BNIP3 suppresses mammary tumorigenesis and metastasis through negative regulation of Warburg effect and HIF-1α. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4316. doi:10.1158/1538-7445.AM2014-4316