bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1646: A glioblastoma methylation assay (GaMA) developedfrom genomic analysis of glioma spheroid cultures predicts response toradiation therapy in patients with glioblastoma
Authors: Wang Qianghu , Ezhilarasan Ravesanker , Eskilsson Eskil , Gumin Joy , Yang Jie , Jaffari Mona , Tang Ming , Aldape Kenneth D. , Lang Frederick F. , Verhaak Roel G.W. , Sulman Erik P. 
Published: July 2016

Abstract
Radiation therapy (RT) remains one of the most effective treatments for patients with GBM and has been repeatedly demonstrated to improve survival; yet response to RT is variable. We explored the relationship between methylation status and radiation response to develop a predictor of RT response using the epigenetic data of glioma sphere-forming cells (GSCs). The DNA methylomes of 42 GSCs were profiled using Illumina Infinium 450K methylation bead arrays. 15 GSCs were irradiated with 2-, 4-, and 6-Gy RT and response determined using clonogenic assays. We discovered 168 CpG probes capable of distinguishing sensitive from resistant GSCs. To validate, we analyzed 362 TCGA GBM samples, 272 that received standard 60Gy RT and 90 treated with low or no RT. Using the glioblastoma methylation assay (GaMA) signature, we classified the samples as either RT sensitive or resistant. Survival was significantly different between the predicted sensitive vs resistant patients for those treated with standard RT (median 21.0m vs 14.7m, p&lt;0.005). GaMA did not predict a survival difference among patients receiving no/low-dose RT, suggesting a predictive, but not prognostic, role for the signature. Using the ENCODE ChIP-Seq Significance Tool, we observed that the transcription factor EZH2 was significantly associated with the radiation resistant promoters in the GaMA signature. Among the hypermethylated genes with EZH2 binding sites, the NR2F2 promoter had the greatest number of hypermethylated CpG sites correlated to RT resistance. NR2F2 has previously been identified as negatively associated with activation of the wnt/β-catenin, a pathway associated with RT resistance of mammary progenitor cells. Expression of WNT1 in TCGA GBM cohort was negatively associated with NR2F2 expression. Our GSC RT response-based methylome analysis corroborates this association and provides a rationale for the methylation signature as a predictive biomarker of radiation response.
Citation Format: Qianghu Wang, Ravesanker Ezhilarasan, Eskil Eskilsson, Joy Gumin, Jie Yang, Mona Jaffari, Ming Tang, Kenneth D. Aldape, Frederick F. Lang, Roel G.W. Verhaak, Erik P. Sulman. A glioblastoma methylation assay (GaMA) developedfrom genomic analysis of glioma spheroid cultures predicts response toradiation therapy in patients with glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1646.
Abstract 1651: Overexpression of hepatoma upregulated protein (HURP) promotes radioresistance in prostate cancer cells
Authors: Hassan Mohamed , El Khattouti Abdelouahid , Ma Tangeng , Espinoza Ingrid , Day W. Andrew , Vijayakumar Srinivasan , Gomez Christian R. 
Published: July 2016

Abstract
Despite progression in diagnosis and treatment, prostate cancer (PCa) still represents major cause of cancer-related mortality and morbidity in men. Although radiation therapy offers clinical benefit over other therapeutic modalities, the success of this therapeutic modality is commonly hampered by significant resistance in advanced tumor. So far, the mechanisms governing the acquired resistance to radiotherapy have not been discussed in detail. Hepatoma Up-Regulated Protein (HURP) is a cell cycle-regulated and microtubule-associated protein. It functions as a Ran GTPase effector and is involved in the stabilization of the mitotic kinetochore fibers. The expression of this protein is elevated in different tumor types and associated with tumor progression and aggressiveness. We recently reported on the value of HURP as an independent prognostic factor for high-risk PCa. The aim of this study was to address the role of HURP in the modulation of PCa resistance to γ- irradiation. Cell lines (LNCaP, PC3, and DU145) with regulated expression of HURP protein using a Lent viral Tet-On 3G Inducible Expression System were irradiated using a Cs-137 γ-source. Overexpression of HURP suppressed γ- irradiation- induced apoptosis. This suppression was associated with the expression of E2F1, p53, p21 together with the phosphorylation of apoptosis signal-regulating kinase1 (ASK1), c-jun-N-terminal kinase (JNK) and Ataxia-telangiectasia mutated (ATM) and histone family member X (H2AX). Also, inhibition of γ- irradiation- induced- cytochrome c release, cleavage of caspase-9, caspase-3, PARP, and reactive oxygen species (ROS) was noted. The observed resistance was consequence of HURP's ability to trigger the ubiquitination of p53 and ATM that, in turn, resulted in the inhibition of downstream pathways, which are essential for the modulation of γ- irradiation-induced apoptosis. Our data provide evidence for the involvement of HURP in the modulation of PCa cell resistance to γ-irradiation via a mechanism mediated by ubiquitination of ATM and p53. Understanding of the biological mechanisms underlying HURP-mediated resistance of PCa to available therapies may help to improve the treatment strategy and emphasize HURP as therapeutic target for PCa treatment.
Funding sources: Department of Defense Grant PC094680 and Prostate Cancer Foundation Creativity Award.
Citation Format: Mohamed Hassan, Abdelouahid El Khattouti, Tangeng Ma, Ingrid Espinoza, W. Andrew Day, Srinivasan Vijayakumar, Christian R. Gomez. Overexpression of hepatoma upregulated protein (HURP) promotes radioresistance in prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1651.
Abstract 166: Optimizing the detection of subclonal somatic variants with VarDict
Authors: Lai Zhongwu , Chapman Brad , Ahdesmäki Miika , Hofmann Oliver , Johnson Justin , Dry Jonathan 
Published: July 2016

Abstract
Detection of somatic variants in tumor tissues is far from a solved problem. Heterogenous tumor materials complicate variant assessment in low frequency subclonal populations, which can play an important role in the development of drug resistance. Loss of heterozygosity, copy number variation and other ploidy changes can further change the expected distribution of variant metrics.
We demonstrate improvements in the specificity and sensitivity of variant calling algorithms by optimising linear combinations of widely used filtering criteria such as allelic frequency, depth and p-value distributions. We specifically improve SNP and indels from the freely available VarDict caller (https://github.com/AstraZeneca-NGS/VarDictJava) and show that these optimisations can be generalised across a wide range of allelic frequencies. We validate our findings against synthetic and in vitro standards such as the ICGC-TCGA DREAM challenge truth set. Our proposed filtering strategy is widely applicable to other variant callers, and the updated filters for VarDict dramatically improve sensitivity and precision on low frequency variants which are crucial for our ability to reconstruct likely tumor populations from short read sequencing data and to study tumor evolution.
Citation Format: Zhongwu Lai, Brad Chapman, Miika Ahdesmäki, Oliver Hofmann, Justin Johnson, Jonathan Dry. Optimizing the detection of subclonal somatic variants with VarDict. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 166.
Abstract 1664: Alpha-tocopheryloxyacetic acid (aTEA) induced immune activation synergizes with radiation therapy to treat primary and metastatic murine mammary carcinoma
Authors: Walker Joshua M. , Barragan Diego M. , Kasiewicz Melissa J. , Thomas Charles R. , Redmond William L. 
Published: July 2016

Abstract
Immunotherapy has now emerged as a promising treatment for metastatic cancer. However, immunotherapy for advanced stage breast carcinoma remains an unmet need. Here we demonstrate that the novel immunomodulator alpha-tocopheryloxyacetic acid (aTEA) synergizes with radiation therapy (RT) in a metastatic murine mammary carcinoma model to improve tumor control more than each individual therapy, and we propose a mechanism based on the stimulation of type I interferons by aTEA.
For in-vivo studies, C57BL/6 mice bearing 4T1 murine mammary carcinoma lesions were treated with dietary aTEA, 20 Gy x 2 fractions ionizing radiotherapy, or the combination of aTEA/RT. Immune activation in animals treated with dietary aTEA was determined by analyzing the percentage of proliferating CD4 and CD8 T cells using a Ki-67 assay. Pulmonary metastatic burden was determined using a clonogenic metastasis assay. For in-vitro studies, murine mammary carcinoma cell lines were treated with aTEA or LPS and whole cell lysates were analyzed by Western blot. Expression of interferon regulation factor 3 (IRF3) pathway proteins, including phospho-TANK binding protein kinase 1 (TBK1) and stimulator of interferon genes (STING) were determined.
Our results indicate that treatment with the combination of aTEA and RT significantly improves tumor control compared to either treatment alone. Combination therapy resulted in complete and durable tumor regression in a subset of animals treated, an effect not observed with aTEA or RT alone. Dietary administration of aTEA stimulates proliferation of both CD4 and CD8 T cells and significantly reduces metastatic burden in 4T1 tumor bearing mice. This immune stimulatory effect of aTEA appears to be mediated by reactive oxygen species (ROS) production and release of type I interferons through a STING mediated pathway.
These preliminary results suggest that the combination of aTEA and ionizing radiation may be a viable therapy for the treatment of metastatic breast carcinoma. This therapeutic combination may provide more durable response to radiotherapy while simultaneously reducing further metastatic spread.
Citation Format: Joshua M. Walker, Diego M. Barragan, Melissa J. Kasiewicz, Charles R. Thomas, William L. Redmond. Alpha-tocopheryloxyacetic acid (aTEA) induced immune activation synergizes with radiation therapy to treat primary and metastatic murine mammary carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1664.
Abstract 169: Drug resistance gene expression pathways in primary refractory breast cancer
Authors: Kan Charlene , Parsai Shikha , Avril Stefanie , Lyons Janice , Gilmore Hannah , Zhang Junran , Harris Lyndsay 
Published: July 2016

Abstract
Purpose/Objective:
Breast cancer is a collection of diseases with distinct molecular subtypes with differing prognoses. Clinically, there is a group of therapy resistant breast cancers characterized by resistance to conventional chemo- and radiotherapy with short overall survival and poor prognosis, which we termed primary refractory breast cancer (PRBC). We hypothesized that PRBC is characterized by specific genomic changes that may contribute to therapy resistance. The aim of this study was to identify changes in gene expression profiles of PRBC compared to triple negative (TNBC) and ER+/-PR positive (HR) breast cancer cohorts.
Methods:
PRBC was defined as patients with an initial diagnosis of Stage I-III breast cancer who either I) developed metastatic disease within 6 months of completing treatment or II) died of breast cancer within two years of initial diagnosis. Formalin-fixed paraffin-embedded (FFPE) tissue was obtained under an IRB approved protocol 01-13-43c. RNA was extracted from macro-dissected FFPE tumor tissue. Gene expression profiling was performed with Affymetrix Human Transcriptome Array 2.0 and gene signatures were analyzed using a single sample gene set enrichment methodology. Gene signatures of PRBC patients were compared to signatures of two TNBC and HR cohorts with gene expression data generated by identical methodology.
Results:
A total of nineteen samples from eight patients had sufficient tumor material to obtain RNA. The median age at diagnosis was 44.3 years, 62.5% were triple negative. At initial diagnosis the stage ranged from IA to IIIC. Sixty-three percent received neoadjuvant chemotherapy. The median time to relapse was 8.4 months and median time to death 1.7 years. Genomic analysis identified highly significant (p&lt;10-6) increased expression of ABC transporters, hypoxia, interferon, DNA repair and AKT signatures compared to control cohorts.
Conclusions:
PRBC is characterized by significant upregulation of multiple gene expression signatures important in drug resistance including ABC transporters, hypoxia, AKT and DNA repair pathways. Confirmation of these results would allow the development of alternative treatment strategies for PRBC to help improve the devastatingly poor prognosis of this subgroup of patients.
Citation Format: Charlene Kan, Shikha Parsai, Stefanie Avril, Janice Lyons, Hannah Gilmore, Junran Zhang, Lyndsay Harris. Drug resistance gene expression pathways in primary refractory breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 169.
Abstract 1700: Novel microfluidic blood-brain niche to study breast cancer metastasis to the brain
Authors: Altemus Megan , Leung Brendan , Morikawa Aki , Dziubinski Michele , Castro Maria , Merajver Sofia 
Published: July 2016

Abstract
Metastasis from the primary tumor site to the brain is the most lethal complication of advanced cancer. Once a patient has developed brain metastasis, treatment involves surgical resection or radiation and is often only palliative. Poor prognosis following these therapies as well as the presence of concurrent disease outside of the nervous system emphasize the need for new systemic therapies that can reach and are active within the brain. In order to study the process of brain metastasis and develop potential therapies, models that mimic the human blood-brain niche must be used. Models currently utilized are murine in vivo models and various in vitro methods that do not accommodate all the biophysical characteristics of a blood-brain barrier. In vivo murine models are costly, time intensive, very slow to manifest metastases, and the metastatic process is seldom amenable to monitoring in real time. Current in vitro models are faster and more cost effective; however the models currently used do not have the same micro-environment complexity as “live” models. Here we describe a novel microfluidic device that accurately mimics the physical and cellular components of the human blood-brain niche to study the brain metastatic process.
This device is composed of two chambers separated by a porous membrane. The top chamber and apical side of the membrane is seeded with human brain endothelial cells with and uses flow to mimic shear stress encountered within the vasculature. Cancer cells are introduced into this chamber in which they adhere to and migrate through the endothelium into the bottom chamber. The bottom chamber contains astrocytes suspended in a collagen gel to mimic the brain stroma and provide room for invading cancer cells to colonize and grow. Barrier integrity is monitored using TEER (trans-endothelial electrical resistance), and fluctuates as the tight junctions of the endothelium are compromised by invading cancer cells. Throughout all time points, from introduction into the flow chamber, adherence to the endothelium, extravasation through the barrier, migration into the stroma, and proliferation the cancer cells can be monitored via microscopy or TEER.
This device provides a powerful novel tool to study the brain metastatic process and can be used to determine differences in brain metastatic potential of various cell lines or patient derived material, study the molecular mechanisms that promote brain metastasis, and test potential new therapies.
Citation Format: Megan Altemus, Brendan Leung, Aki Morikawa, Michele Dziubinski, Maria Castro, Sofia Merajver. Novel microfluidic blood-brain niche to study breast cancer metastasis to the brain. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1700.
Abstract 1702: Sucrose nonfermenting 1-related kinase (SNRK) expression in ovarian cancer and correlation with clinical features
Authors: Hopp Elizabeth E. , Bishop Erin , Cossette Stephanie , Ramchandran Ramani 
Published: July 2016

Abstract
Objective: Human omental adipocytes promote migration and invasion of ovarian cancer cells and result in alterations in metabolism including increased AMP-activated protein kinase (AMPK) and b-oxidation, which allow for use of lipids as an energy source. Sucrose nonfermenting 1-related kinase (SNRK) is a member of the AMPK family of serine/threonine kinases, which are activated by starvation and stress conditions. The goal of this study is to describe the expression of SNRK in human ovarian cancer tissue.
Methods: Tissue was collected from patients undergoing surgery for serous ovarian cancer or benign indications. Immunohistochemistry (IHC) was used to detect SNRK expression. SNRK+ cells were compared between benign and malignant tissue, and statistical significance between positivity and clinicopathologic variables was determined using the Mann-Whitney U test.
Results: In the 31 samples analyzed, SNRK demonstrates a nuclear staining pattern. IHC shows increased SNRK+ cells in malignant tissue versus benign tissue (42.0% versus 31.3% positive nuclei, p&lt;0.001). When examining patient characteristics, the malignant samples with the lowest percentage of SNRK+ nuclei were stage IIIB-IV with a high incidence of recurrence and death due to disease.
Conclusions: This is the first study to describe SNRK expression in ovarian cancer tissue. We show that SNRK has a nuclear staining pattern and that expression is greater in malignant ovarian tissue compared to benign ovarian tissue, which may be due to more metabolic stress on cells with higher proliferation rates. SNRK expression appears to be lower in those with a higher disease stage and poor outcome potentially secondary to metabolic changes that occur once the disease metastasizes. We are currently examining SNRK expression in metastatic omental tumors in order to further explore expression differences between primary versus metastatic disease sites.
Citation Format: Elizabeth E. Hopp, Erin Bishop, Stephanie Cossette, Ramani Ramchandran. Sucrose nonfermenting 1-related kinase (SNRK) expression in ovarian cancer and correlation with clinical features. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1702.
Abstract 1751: Coffee and tea intake and risk of endometrial cancer in the Epidemiology of Endometrial Cancer Consortium (E2C2)
Authors: Crous-Bou Marta ,   Epidemiology of Endometrial Cancer Consortium (E2C2), De Vivo Immaculata 
Published: July 2016

Abstract
Background: Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. Well-known risk factors for EC include obesity and elevated levels of estrogen and insulin. Coffee and tea are the most widely consumed beverages in the world, after water. Both are a complex mixture of chemicals with potential antimutagenic and antioxidant properties. Previous studies have reported an inverse association between coffee consumption and circulating levels of estrogen and C-peptide, a marker of insulin secretion, both involved in endometrial carcinogenesis. The presence of antioxidants and other chemopreventive compounds in coffee and tea may have an anticarcinogenic effect. Thus, coffee and tea drinking may decrease the risk of EC.
Objective: To examine the association between coffee and tea intake and endometrial cancer risk.
Patients and Methods: We combined individual-level data from 24 epidemiologic studies (10 Cohort studies, 14 Case-Control studies) from the Epidemiology of Endometrial Cancer (E2C2) Consortium and performed a pooled analysis of 11,424 endometrial cancer cases and 28,388 controls. Logistic regression models were used to calculate ORs and the corresponding 95% CI. All models were adjusted for potential confounders.
Results and Conclusions: Increased coffee consumption was associated with a reduced risk of endometrial cancer: compared to non-coffee drinkers, the pooled OR for those who drank more than 1 cup of coffee per day was 0.79 (95%CI = 0.71-0.87, p = 5.48×10−6). The association is mainly observed in cohort studies and remains significant after adjusting for potential confounders. We found no association between tea consumption and endometrial cancer risk.
Citation Format: Marta Crous-Bou, Epidemiology of Endometrial Cancer Consortium (E2C2), Immaculata De Vivo. Coffee and tea intake and risk of endometrial cancer in the Epidemiology of Endometrial Cancer Consortium (E2C2). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1751.