bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 762: The interleukin-1 inflammatory cytokine family modulates p62/SQSTM1 accumulation in breast cancer cell lines
Authors: Fathima Nawas Afshan , Ramachandran Janani , Thomas Shayna , Ravichandran Jananisree , Delk Nikki 
Published: July 2016

Abstract
Tumors are likened to wounds that do not heal. Thus, not surprisingly, inflammatory cytokines are present in the primary and metastatic tumor microenvironments due, in part, to infiltrating bone-derived cells (e.g., macrophages). We previously discovered that a bone marrow stromal cell line that secretes the inflammatory cytokine, interleukin-1 beta (IL-1â), upregulates p62 mRNA and protein in prostate cancer cell lines and we showed that p62 can be cytoprotective for prostate cancer cells. p62/Sequestome-1 is a multifunctional scaffold protein that can be seen microscopically as subcellular “speckles” which serve as organizing centers for multiple different signaling cascades, ranging from autophagy-mediated degradation of ubiquitinated proteins to KEAP1-NRF2 antioxidant response. To determine if our previous discoveries might be cancer-type specific and to test our hypothesis that p62 promotes cancer cell survival in response to inflammatory cytokines, we expanded our studies to various breast cancer cell lines of varying receptor status, including ZR57-1, T47D, and MDA-MB-468 and determined cell response two interleukin-1 family members, alpha (á) and beta (â). We treated the breast cancer cells with IL-1á and/or IL-1â and analyzed p62 mRNA and protein levels, subcellular localization, and protein-protein interactions. IL-1á and IL-1â can induce p62 speckle accumulation that can be seen to co-localize with the autophagosome membrane protein, LC3B, suggesting an autophagy-dependent regulation and/or function for p62. In addition, p62 co-immunoprecipitates with KEAP1, suggesting a KEAP1-NRF2-dependent antioxidant function for p62. Taken together, our data implies that cancer cells usurp inflammatory cytokines, such as IL-1, present in the primary or metastatic tumor microenvironment to promote cell survival through proteins such as p62.
Citation Format: Afshan Fathima Nawas, Janani Ramachandran, Shayna Thomas, Jananisree Ravichandran, Nikki Delk. The interleukin-1 inflammatory cytokine family modulates p62/SQSTM1 accumulation in breast cancer cell lines. [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 762.
Abstract 763: Exosomal miR-6126 as a novel tumor suppressor in ovarian cancer
Authors: Kanlikilicer Pinar , Rashed Mohammed Mohammed H. S. , Bayraktar Recep , Mitra Rahul , Ivan Cristina , Aslan Burcu , Zhang Xinna , Cristian Rodriguez-Aguayo , Bayraktar Emine , Picher Martin , Ozpolat Bulent , Calin George A. , Sood Anil K. , Lopez-Berestein Gabriel 
Published: July 2016

Abstract
Tumor microenvironment has been known to play a key role in cancer by the development of drug resistance, epithelial-mesenchymal transition, metastasis and angiogenesis. There is emerging evidence that cancer originated exosomes may contribute to the tumor microenvironment to promote tumorigenesis. Exosomes are nano-sized vesicles that contain non-coding RNAs such as miRNAs or siRNAs. Non-coding RNAs are involved in the pathogenesis of the majority of cancer and reveals a new layer of complexity in the molecular architecture of tumorigenicity. The purpose of this study is to identify miRNA content of both sensitive and resistant ovarian cancer-cell derived exosomes for the identification of exosomal RNA-mediated tumorigenesis in ovarian cancer. Using miRNA microarray profiling, we identified differentially expressed exosomal miRNAs in three sensitive (Heya8, Skov3, A2780) and resistant (Heya8-MDR, Skov3-TR, A2780-CP20) isogenic ovarian cancer cell lines. miR-6126 was found to be only miRNA significantly up-regulated in all cancer cell exosomes released to tumor microenvironment. In vitro functional assays showed that miR-6126 act as a tumor suppressor by inhibiting proliferation, migration, invasion and tube formation. miR-6126 acts as a novel potential tumor suppressor through targeting integrin beta-1, leading to inhibition of PI3K/AKT and Ras/Raf signaling. In vivo experiments also demonstrated that administration of miR-6126 into the nude mice with established tumors inhibited tumor weight. Immunohistochemistry results showed that miR-6126 treatment inhibits many oncogenic functions such as proliferation and angiogenesis of ovarian cancer. We believe that these findings help the identification of exosomal RNA-mediated tumorigenesis in ovarian cancer.
Citation Format: Pinar Kanlikilicer, Mohammed Mohammed H. S. Rashed, Recep Bayraktar, Rahul Mitra, Cristina Ivan, Burcu Aslan, Xinna Zhang, Rodriguez-Aguayo Cristian, Emine Bayraktar, Martin Picher, Bulent Ozpolat, George A. Calin, Anil K. Sood, Gabriel Lopez-Berestein. Exosomal miR-6126 as a novel tumor suppressor in ovarian 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 763.
Abstract 764: LOX and LOXL2 inhibition as a treatment for ovarian cancer
Authors: Cho Angela , Hudson Amanda L. , Yuen Samuel , Tran Nham , Howell Viive M. , Colvin Emily K. 
Published: July 2016

Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy in women. Despite advances in our understanding of the molecular biology of EOC, patient survival has not significantly improved in decades and new treatments are needed. There is increased interest in therapeutic targeting of the tumor microenvironment (TME). The lysyl oxidase (LOX) family of enzymes are involved in extracellular matrix remodelling through crosslinking of collagen and elastin. They have been shown to play an important role in the TME of other cancers and are regulated by hypoxia, however little is known about their role in EOC. Therefore we aimed to investigate the role of LOX and LOXL2 in EOC using in vitro models.
Tumor epithelial (n = 2) and matched cancer-associated fibroblast cell lines (n = 2) derived from an SV40-induced mouse model of EOC were generated. MTT assays were performed on all cell lines to assess the effect of LOX and LOXL2 inhibition on cell viability. The effect of LOX and LOXL2 inhibition on cancer cell migration and invasion towards cancer-associated fibroblast conditioned media was also investigated using transwell assays. RNA and protein were isolated and analysed from cells cultured in normoxic and hypoxic conditions to assess whether LOX and LOXL2 gene and protein expression is regulated by hypoxia.
Inhibition of LOX and LOXL2 did not affect cell viability. LOX and LOXL2 inhibition significantly reduced the migration and invasion of EOC cells towards cancer-associated fibroblast conditioned media in vitro (p&lt;0.05). Gene expression analysis comparing Lox and Loxl2 expression in all cell lines demonstrated a significant increase in Lox and Loxl2 expression in cells cultured in hypoxia (p&lt;0.05). Similarly, cellular and secreted LOX and LOXL2 protein expression was increased in cells cultured in hypoxic conditions, supporting hypoxia as a regulator of LOX and LOXL2 expression.
This study demonstrates a role for LOX and LOXL2 in promoting migration and invasion of EOC cells in vitro. The upregulation of LOX and LOXL2 in hypoxia suggests a role in facilitating tumor growth and progression within hypoxic tumors. These results provide support for the utility of LOX and LOXL2 inhibition as promising and novel therapeutic strategies in EOC.
Citation Format: Angela Cho, Amanda L. Hudson, Samuel Yuen, Nham Tran, Viive M. Howell, Emily K. Colvin. LOX and LOXL2 inhibition as a treatment for ovarian 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 764.
Abstract 767: TCR sequencing can identify and track tumor-specific T cell populations and is a predictive biomarker of response to DC vaccination in glioblastoma patients
Authors: Sedighim Shaina , Hsu Melody , Wang Tina , Everson Richard G. , Tucker Alex , Antonios Joseph P. , Du Lin , Emerson Ryan , Yusko Erik , Sanders Catherine , Robins Harlan , Yong William , Davidson Tom B. , Li Gang , Liau Linda M. , Prins Robert 
Published: July 2016

Abstract
While immunotherapeutic strategies are emerging adjunctive treatments for cancer, sensitive methods of monitoring the immune response after treatment remain to be established. We used a novel next generation sequencing (NGS) approach to determine whether quantitative assessments of tumor infiltrating lymphocyte (TIL) content and the degree of overlap of T cell receptor (TCR) sequences in brain tumors and peripheral blood were predictors of immune response and overall survival in glioblastoma (GBM) patients treated with autologous tumor lysate-pulsed dendritic cell (DC) immunotherapy. A significant correlation was found between a higher estimated TIL content and increased time to progression (TTP) and overall survival (OS). In addition, we were able to assess the proportion of shared TCR sequences between tumor and peripheral blood at time points before and after therapy, and found the level of TCR overlap to correlate with survival outcomes. Higher degrees of overlap, or the development of an increased overlap following immunotherapy, correlated with improved clinical outcome, and may provide insights into the successful, antigen-specific immune response.
Citation Format: Shaina Sedighim, Melody Hsu, Tina Wang, Richard G. Everson, Alex Tucker, Joseph P. Antonios, Lin Du, Ryan Emerson, Erik Yusko, Catherine Sanders, Harlan Robins, William Yong, Tom B. Davidson, Gang Li, Linda M. Liau, Robert Prins. TCR sequencing can identify and track tumor-specific T cell populations and is a predictive biomarker of response to DC vaccination in glioblastoma patients. [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 767.
Abstract 770: Negative regulation of the CCL22/CCR4 axis by TNFR1 improves melanoma outcome
Authors: Leite Caio Abner , Melo Paulo Henrique , Mota Jose Mauricio , Prado Douglas Silva , Viacava Paula Ramos , Cunha Fernando Queiroz , Alves Filho Jose Carlos 
Published: July 2016

Abstract
Purpose: Immunotherapy for melanoma skin cancer is mainly focused on preventing T cell deactivation through PD1 or CTLA4 inhibition. Another proposed mechanism to increase global T cell response is to prevent Treg immunossupressive function through TNFR1/TNF activation or CCR4/CCL22 inhibition. We aimed to evaluate the role of TNFR1 and CCR4 in an experimental model of melanoma.
Experimental procedures: C57/Bl6 WT, TNFR1 -/- or CCR4 -/- mice were subcutaneously inoculated with 30,000 B16-F10 cells for tumor growth measurement and survival analysis. In a different set of experiments, mice were euthanized fourteen days after inoculation (D14) for spleen, lymph nodes and tumor harvesting for Treg (CD4+CD25+FoxP3+) and TAM (CD45+F4/80+CD206+) quantification by flow cytometry. CCL22 concentrations were quantified in conditioned media from bone marrow-derived macrophages (BMDM) from WT, or TNFR1 -/- mice. Furthermore, TNFR1 and CCR4 gene expression in human melanoma was determined by data mining in deposited datasets (GSE46517).
Results: TNFR1-/- showed increased tumor volumes and reduced survival when compared to their WT counterparts. At D14, we detected increased Treg and TAM accumulation in TNFR1-/- tumor microenvironment. CCL22 concentrations were increased in conditioned media from M2-polarized BMDM from TNFR1-/- mice. CCR4 deficient mice presented reduced tumor volumes and increased survival, accompanied by a reduced Treg accumulation at D14. Data mining in GEO gene expression bank revealed that metastatic melanoma presented reduced TNFR1 and increased CCR4 expression.
Conclusions: CCR4 inhibition is a potential strategy to reduce Treg accumulation and improve outcomes in cancer patients. Further assessments are required to demonstrate the role of TNFR1 pathway in CCR4 activation.
Citation Format: Caio Abner Leite, Paulo Henrique Melo, Jose Mauricio Mota, Douglas Silva Prado, Paula Ramos Viacava, Fernando Queiroz Cunha, Jose Carlos Alves Filho. Negative regulation of the CCL22/CCR4 axis by TNFR1 improves melanoma outcome. [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 770.
Abstract 775: Combinatorial compound stratification based on integration of LINCS, TCGA and PubChem data
Authors: Stathias Vasileios , Allen Bryce , Clarke Jennifer , Ayad Nagi G. , Schürer Stephan 
Published: July 2016

Abstract
The purpose of this study is to leverage the large number of perturbation signatures from the NIH Library of Integrative Network-based Cellular Signatures (LINCS) and integrate them with patient data from The Cancer Genome Atlas (TCGA) and PubChem bioactivity data in an effort to prioritize compounds based on their synergistic effect in cancer treatment.
From the large number of LINCS L1000 transcriptional data capturing cellular responses after chemical or genetic perturbations, we extracted gene expression signatures that were indicative of specific LINCS compounds. Moreover, we compared the L1000 transcriptional profiles with ones from TCGA in order to identify characteristic signatures of major cancer types and prioritized small molecule compounds with discordant expression profiles to those cancer types. We then linked the above compounds to protein target annotations and therefore produced a compound-specific protein target profile. For this, we utilized biochemical data produced by the LINCS KinomeScan and KiNative assays and also biochemical data obtained through PubChem. Using the above information, we obtained pairs of compounds that would inhibit unlinked gene sub-networks that were produced through processing of the TCGA transcriptional data.
The above process can be used as a means to suggest compound combinations towards specific cancer types and to prioritize the development of compounds with targeted polypharmacology.
Citation Format: Vasileios Stathias, Bryce Allen, Jennifer Clarke, Nagi G. Ayad, Stephan Schürer. Combinatorial compound stratification based on integration of LINCS, TCGA and PubChem data. [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 775.
Abstract 785: The prepubertal mammary gland transcriptome suggests a role for the immune system in hormone-independent breast cancer
Authors: Stires Hillary , Crismale-Gann Catina , Belden William J. , Cohick Wendie S. 
Published: July 2016

Abstract
Identifying signaling pathways involved in mammary gland development has contributed to our understanding of breast cancer. While growth of the gland is isometric between birth and puberty, ductal expansion is significant and morphological changes such as terminal end bud formation occur during this developmental window. While estrogen receptor alpha (ERá) and progesterone receptor (PR) expression are evident during this time, pre-pubertal levels of free estradiol are low and growth is independent of ovarian hormones. Basal-like breast cancers represent a subset of breast cancers (10-15% of all women with breast cancer) that often lack ERá, PR and HER2 (i.e. triple negative), are ovarian hormone independent, and have a worse prognosis than other tumor subtypes. Animal models for basal-like breast cancer are limited. Therefore identifying gene changes during prepubertal mammary gland development may give insight into the mechanisms that drive these breast cancers. Offspring from individual Sprague Dawley dams were sacrificed on postnatal days (PND) 2, 10 and 20 (n = 5 to 6 for each PND) and the fourth inguinal glands were removed. RNA was isolated and sequenced by RNASeq using 25 million paired end reads. Bioinformatics analysis utilizing TopHat, Bowtie2, and CummeRbund revealed &gt;7000 genes that changed during this time (alpha = 0.05). Analysis by DAVID/KEGG and Ingenuity Pathway Analysis demonstrated differences in immune pathways over time whereby immune genes increased from PND 2 to 10 to 20. Specifically, T Cell Receptor Signaling and B Cell Development were two of the most affected pathways. These results are interesting as recent studies have indicated that the immune system may influence basal-like breast cancers. Molecular signatures defining subtypes of basal-like breast cancer have been described and include basal-like immunosuppressed (BLIS) and basal-like immune activated (BLIA). A better understanding of the role of the immune system in prepubertal mammary gland development may help guide treatment strategies for hormone independent breast cancers.
Citation Format: Hillary Stires, Catina Crismale-Gann, William J. Belden, Wendie S. Cohick. The prepubertal mammary gland transcriptome suggests a role for the immune system in hormone-independent 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 785.
Abstract 786: Project Survival: Interrogative Biology® platform mediated discovery of molecular markers for detection, stratification and outcomes in pancreatic cancer
Authors: Narain Niven R. , Moser A James , Ramanathan Ramesh , Crowley John , Stoll-D’Astice Amy , Sun Yezhou , Rodrigues Leonardo O. , Grund Eric M. , Chen Emily , Vishnudas Vivek K. , Kiebish Michael A. , Akmaev Viatcheslav R. , Sarangarajan Rangaprasad 
Published: July 2016

Abstract
Pancreatic adenocarcinoma generally presents with a poor prognosis and an extremely low response rate to first line therapies. There is a critical unmet need to discover and implement effective diagnostic panels to stratify outcomes and tailor treatment strategies to improve survival. The BERG Interrogative Biology® platform utilizes Artificial Intelligence to analyze and integrate multi-omic profiles with clinical annotation to define novel biomarkers and improve treatment interventions. Herein, we analyzed the serum proteome, signaling lipidome, structural lipidome, and metabolome of 163patients at multiple timepoints (pancreatic cancer: 115; pancreatitis: 15; and age-matched healthy controls: 33). Utilizing the power of the Bayesian Network learner, bAIcis™ (BERG Artificial Intelligence Clinical Information System), multi-omic profiles were aligned to the longitudinal clinical information and subjected to AI-algorithms to infer probabilistic cause-and-effect relationships among molecular and clinical variables explicitly explaining pancreatic cancer status, cancer progression, and survival, and defining the interconnectivity of molecular features with clinical phenotype. Network features linking into clinical endpoints and key network pressure points were identified as molecular drivers. The drivers of clinical endpoints were analyzed to rank potential biomarkers. Novel biomarkers were discovered that demonstrate diagnostic potential for pancreatic cancer detection, disease prognosis including metastatic disease progression, patient stratification associated with survival, and response to standard chemotherapy agents like Gemcitibine. A prospective study is underway to validate the biomarkers and discover additional diagnostic and therapeutic molecules to improve the outcomes for patients affected by adenocarcinoma of the pancreas.
Citation Format: Niven R. Narain, A James Moser, Ramesh Ramanathan, John Crowley, Amy Stoll-D’Astice, Yezhou Sun, Leonardo O. Rodrigues, Eric M. Grund, Emily Chen, Vivek K. Vishnudas, Michael A. Kiebish, Viatcheslav R. Akmaev, Rangaprasad Sarangarajan. Project Survival: Interrogative Biology® platform mediated discovery of molecular markers for detection, stratification and outcomes in pancreatic 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 786.
Abstract 792: Super-transactivation TP53 variant in the germline of a family with Li-Fraumeni variant
Authors: Id Said Badr , Kim Han , Tran James , Novokmet Ana , Malkin David 
Published: July 2016

Abstract
Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant familial cancer syndrome, characterized by multiple malignancies and frequent germline alterations in TP53. In this study, we highlight four unclassified exonic p53 variants detected in patients with a suspected diagnosis of LFS. We report for the first time the discovery of two novel functional variants in codons 191(c.572C&gt;G; p.P191R) and 360 (c.1079G&gt;T; p.G360V), located, respectively, in the DNA binding domain and in a linker region near the tetramerization domain of TP53. Our data revealed that while the P191R variant decreased the transactivation levels of several p53 targets, it failed to segregate with the disease state. The G360V variant, on the other hand, behaved in a paradoxical fashion by causing a stark upregulation in the activity of several p53 response elements. This tumor suppressive effect was also observed at the level of colony formation and c-Caspase 3 activation. While unlikely to be disease-causing, we propose that these variants may represent novel p53 polymorphisms and potential phenotypic modifiers in LFS. In the future, the enhanced transactivation effects of G360V-p53 may also prove useful in designing more efficacious p53-based gene therapies.
Citation Format: Badr Id Said, Han Kim, James Tran, Ana Novokmet, David Malkin. Super-transactivation TP53 variant in the germline of a family with Li-Fraumeni variant. [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 792.