tbuckley/cabot-search huggingface dataset:
Abstract 3879: Expression of sox2 and oct4 in human oral squamous cell carcinoma and its relationship with clinical factors
Authors: Tetsuya Tamatani, Natsumi Takamaru, Go Ohe, Keiko Kudo, Takaharu Kudo, Akira Takahashi, Yoshiko Yamamura, Kenji Fujisawa, Hirokazu Nagai, Youji Miyamoto
Journal: Cancer Research (2017)

Abstract Background: A cancer stem cell (cancer initiating cell, CSC) is considered capable of self -replication, self-differentiation, drug resistance, and immune evasion. Recently, CSC has become increasingly important in the treatment of malignant tumors. Cancer stem cells express specific molecules termed CSC marker, including sex determining region Y-box2 (SOX2), and octamer-binding transcription factor 4 (Oct4), and their expression has been reported to be the potential prognostic values. However, the prognostic values of SOX2 and Oct4 expression in patients with oral cancer are less understood. [Purpose]The aims of present study were to evaluate the expression of SOX2 and Oct4 in oral squamous cell carcinoma (OSCC) and to elucidate the relationships among the CSC marker expression, clinical stages, histological differentiation, the classification of invasion mode, cerebral lymph node metastasis, distant metastasis, and disease-free survival rate. Materials and Methods: Tissue specimens were obtains from 108 patients with OSCC after surgery or biopsy. Immunohistochemistry was used to assess SOX2 and Oct4 protein using at least 10% staining-positive cells as the definition of positive staining. Results: Immunohistochemical analysis of 108 cases showed that 42 cases (39%) expressed SOX2. There was no significant association between SOX2 expression and tumor size, invasion mode or histological differentiation. However, there was significant association between SOX2 expression and distant metastasis or disease-free survival rate at stage 1 and 2 patients (73 cases). Otherwise, seventy cases (65%) cases of 108 OSCC patients expressed Oct4. There was significant association between Oct4 expression and histological differentiation. There was no significant association between Oct4 expression and tumor size, invasion mode, metastasis, or disease-free survival rate. Conclusions: These findings suggested that the expression of SOX2 may be good marker indicating survival in patients with OSCC. Citation Format: Tetsuya Tamatani, Natsumi Takamaru, Go Ohe, Keiko Kudo, Takaharu Kudo, Akira Takahashi, Yoshiko Yamamura, Kenji Fujisawa, Hirokazu Nagai, Youji Miyamoto. Expression of sox2 and oct4 in human oral squamous cell carcinoma and its relationship with clinical factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3879. doi:10.1158/1538-7445.AM2017-3879
RF magnetron-sputtered coatings deposited from biphasic calcium phosphate targets for biomedical implant applications
Authors: K.A. Prosolov, K.S. Popova, O.A. Belyavskaya, J.V. Rau, K.A. Gross, A. Ubelis, Yu.P. Sharkeev
Journal: Bioactive Materials (2017)

Bioactive calcium phosphate coatings were deposited by radio-frequency magnetron sputtering from biphasic targets of hydroxyapatite and tricalcium phosphate, sintered at different mass % ratios. According to Raman scattering and X-ray diffraction data, the deposited hydroxyapatite coatings have a disordered structure. High-temperature treatment of the coatings in air leads to a transformation of the quasi-amorphous structure into a crystalline one. A correlation has been observed between the increase in the Ca content in the coatings and a subsequent decrease in Ca in the biphasic targets after a series of deposition processes. It was proposed that the addition of tricalcium phosphate to the targets would led to a finer coating's surface topography with the average size of 78 nm for the structural elements.
Toward Precision Radiotherapy for Use with Immune Checkpoint Blockers
Authors: Claire Vanpouille-Box, Silvia C. Formenti, Sandra Demaria
Journal: Clinical Cancer Research (2017)

The first evidence that radiotherapy enhances the efficacy of immune checkpoint blockers (ICB) was obtained a dozen years ago in a mouse model of metastatic carcinoma refractory to anti-CTLA-4 treatment. At the time, ICBs had just entered clinical testing, an endeavor that culminated in 2011 with the approval of the first anti-CTLA-4 antibody for use in metastatic melanoma patients (ipilimumab). Thereafter, some patients progressing on ipilimumab showed systemic responses only upon receiving radiation to one lesion, confirming clinically the proimmunogenic effects of radiation. Preclinical data demonstrate that multiple immunomodulators synergize with radiotherapy to cause the regression of irradiated tumors and, less often, nonirradiated metastases. However, the impact of dose and fractionation on the immunostimulatory potential of radiotherapy has not been thoroughly investigated. This issue is extremely relevant given the growing number of clinical trials testing the ability of radiotherapy to increase the efficacy of ICBs. Recent data demonstrate that the recruitment of dendritic cells to neoplastic lesions (and hence the priming of tumor-specific CD8+ T cells) is highly dependent on radiotherapy dose and fractionation through a mechanism that involves the accumulation of double-stranded DNA in the cytoplasm of cancer cells and consequent type I IFN release. The molecular links between the cellular response to radiotherapy and type I IFN secretion are just being uncovered. Here, we discuss the rationale for an optimized use of radiotherapy as well as candidate biomarkers that may predict clinical responses to radiotherapy combined with ICBs. Clin Cancer Res; 24(2); 259-65. ©2017 AACR.
Abstract 2661: A broad approach for the selection of therapeutic mAbs to TNFR-superfamily members for use in combination with an anti-PD-1 mAb
Authors: Cheng Chen, Xiaoniu Miao, Yao Yan, Liang Tang, Bingliang Chen, Junjian Liu, Xiaolin Liu, Michael Yu, Andy Tsun
Journal: Cancer Research (2017)

Abstract The rise of therapeutic antibodies directed towards T cell checkpoint inhibitors has paved the way to a novel and exciting frontier of cancer treatments. Spearheaded by anti-CTLA-4 and PD-1/PD-L1 inhibitors, many investigators have strived to uncover combinatory therapies that could synergize with CTLA-4 and PD-1 inhibitors to improve the overall survival of cancer patients. The TNFR-superfamily has been seen as an ideal combinatory target in providing co-stimulatory T cell signals in sync with the unleashing of T cells from their CTLA-4 and PD-1 brakes. The ideal outcome of these combinations is the induction of T cell memory and effector function towards tumour cells. Current clinical-stage agents against TNFR-superfamily targets include conventional or Fc-engineered therapeutic antibodies and multimeric ligands that aim to cluster and activate targets such as OX40, 4-1BB, GITR, and CD27. For OX40 and GITR, wildtype IgG1 variants offer target cell depletion of OX40/GITR-high expressing Treg cells, and also provide agonism through FcgR-mediated crosslinking. We have taken a broad approach of screening IgG1, IgG2, Fc-engineered and tetravalent antibodies to select for potent therapeutic antibody candidates to TNFR-superfamily targets, and conducted humanized mouse studies as a screen for candidate potency. Citation Format: Cheng Chen, Xiaoniu Miao, Yao Yan, Liang Tang, Bingliang Chen, Junjian Liu, Xiaolin Liu, Michael Yu, Andy Tsun. A broad approach for the selection of therapeutic mAbs to TNFR-superfamily members for use in combination with an anti-PD-1 mAb [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2661. doi:10.1158/1538-7445.AM2017-2661
Tumor-derived exosomes induce CD8+ T cell suppressors
Authors: Brian T. Maybruck, Lukas W. Pfannenstiel, Marcela Diaz-Montero, Brian R. Gastman
Journal: Journal for ImmunoTherapy of Cancer (2017)

<h3>Background</h3> The suppressive nature of immune cells in the tumor microenvironment plays a major role in regulating anti-tumor immune responses. Our previous work demonstrated that a soluble factor from tumor cells is able to induce a suppressor phenotype (SP) in human CD8<sup>+</sup> T cells typified by loss of CD27/CD28 expression and acquisition of a potent suppressor function. The present study hypothesized that the soluble mechanism that is inducing the SP in CD8<sup>+</sup> T cells are tumor-derived exosomes (TDEs). <h3>Methods</h3> Membrane vesicles and TDEs from multiple head and neck cancer cell line's conditioned growth media were isolated by ultracentrifugation and precipitation, respectively. Human purified CD3<sup>+</sup>CD8<sup>+</sup> T cells were assessed for their induction of the T cell SP by flow cytometry identifying loss of CD27/CD28 expression and in vitro suppression assays. Furthermore, the T cell SP was characterized for the attenuation of IFN-γ production. To delineate exosomal proteins contributing to T cell SP, mass spectrometry was used to identify unique proteins that were present in TDEs. CRISPR/Cas9 knockout constructs were used to examine the role of one of these proteins, galectin-1. To assess the role of exosomal RNA, RNA purified from TDEs was nucleofected into CD8<sup>+</sup> T cells followed by suppression analysis. <h3>Results</h3> Using fractionated conditioned growth media, factors &gt;200&nbsp;kDa induced CD8<sup>+</sup> T cell SP, which was determined to be an exosome by mass spectrometry analysis. Multiple head and neck cancer-derived cell lines were found to secrete T cell SP-inducing exosomes. Mass spectrometry analysis revealed that an immunoregulatory protein, galectin-1 (Gal-1), was expressed in those exosomes, but not in TDEs unable to induce T cell SP. Galectin-1 knockout cells were found to be less able to induce T cell SP. Furthermore, RNA purified from the T cell SP-inducing exosomes were found to partially induce the SP when transfected into normal CD8<sup>+</sup> T cells. <h3>Conclusions</h3> For the first-time, TDEs have been identified to induce a SP in CD8<sup>+</sup> T cells and their mode of action may be synergistic effects from exosomal proteins and RNA. One protein in particular, galectin-1, appears to play a significant role in inducing T cell SP. Therefore, tumor-derived immunosuppressive exosomes are a potential therapeutic target to prevent T cell dysfunction and enhance anti-tumor immune responses.
Abstract 1362: Argonaute 2 controls RAS activation in mouse embryonic fibroblasts
Authors: Ronald F. Siebenaler, Sunita Shankar, Vijaya L. Dommeti, Malay Mody, Arul Chinnaiyan
Journal: Cancer Research (2017)

Abstract The RAS gene family is among the most commonly mutated genes within cancer, and while much research has elucidated the major downstream pathways, including MAPK and PI3K, little progress has been made in successfully targeting mutant RAS in cancer. We recently identified an interaction between the N terminal domain of Argonaute 2 (AGO2), a core component of RNA-induced silencing complex (RISC), and the Switch II domain of KRAS. Furthermore, this interaction was found in all cell lines tested, expressing either wild-type (WT) or mutant KRAS. We found that stable knockdown of AGO2 in KRAS dependent cell lines lead to a decrease in KRAS protein expression with a subsequent decrease in cellular proliferation. Conversely, the overexpression of AGO2 in these cells lead to both an increase in KRAS expression and oncogenesis. In addition, this interaction inhibits the RNAi function of AGO2 by preventing microRNA unwinding in the presence of oncogenic KRAS compared to WT-KRAS. Despite a clear association between mutant KRAS and AGO2 mediating increased KRAS mediated oncogenesis, the precise function of this interaction remains unclear in normal physiology. In order to better assess the endogenous function of the KRAS-AGO2 interaction, we analyzed two mouse embryonic fibroblast cell lines (NIH 3T3 and MEF) with complete knockout of AGO2. Utilizing a Raf-1 RAS binding domain (RBD) pulldown method, we assessed activated WT-RAS levels in AGO2 null NIH 3T3 and MEF cells. We found that knockout of AGO2 lead to an increase in WT RAS-GTP activation compared to normal control cells. Immunoblot analysis also indicates that AGO2 null fibroblasts lead to increase in RAS downstream signaling through the MAPK/ERK and PI3K/AKT pathways. Furthermore, rescue of AGO2 knockout using full length mouse AGO2 decreased wild type RAS activation and its downstream signaling. Taken together, these observations suggest that the AGO2 interaction may suppress WT-KRAS activation, leading to maintenance of RAS-GDP levels. Using RNA-seq, proteome and microRNA analysis, we have begun to identify the pathways that may be involved in RAS activation in AGO2 null cells. Early analyses indicate that AGO2 controls WT-KRAS levels and activity through multiple mechanisms, laying the foundation for a better understanding of the RAS-AGO2 interaction in normal physiology. Citation Format: Ronald F. Siebenaler, Sunita Shankar, Vijaya L. Dommeti, Malay Mody, Arul Chinnaiyan. Argonaute 2 controls RAS activation in mouse embryonic fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1362. doi:10.1158/1538-7445.AM2017-1362
Abstract 2633: Identification of novel T cell co-inhibitory and co-stimulatory receptors from screening a comprehensive library of extracellular proteins
Authors: Arthur Brace, Nathan Sallee, Justin Chou, Lindsay Garrenton, Diana Chen, Ryan Liang, Greg Kemper, David Yang, Marina Jaquez, Janine Powers, Mikayel Mkrtichyan, Thomas Brennan, Luis Borges
Journal: Cancer Research (2017)

Abstract Antibody blockade of immune checkpoint regulators such as PD-1 and CTLA-4 has been shown to be an effective cancer treatment strategy; however, a large percentage of patients still do not respond to existing therapies. Discovery of additional immune checkpoints and co-stimulatory receptors and development of antibody therapeutics against them are likely critical to address this unmet patient need. We generated a comprehensive library of essentially all human extracellular proteins and have used this library to screen for new agents that modulate the function of various immune cell subsets both in vitro and in vivo. Using primary T effector and regulatory T cells, we have identified new targets that modulate the activities of these T cell populations in vitro and are currently evaluating these proteins as possible targets for cancer immunotherapy. In addition, we have expressed a subset of the library in three different models of tumor-bearing mice and have identified several proteins that modulate anti-tumor immunity in vivo. Several of the proteins identified in these screens have activity across multiple primary cell and in vivo tumor model screens and we are rapidly evaluating them as possible targets for novel immuno-oncology therapeutics. Taken together, we believe that we have developed robust in vitro and in vivo platforms that will allow us to discover novel cancer immuno-therapeutics that will help address the needs of cancer patients that fail to respond to current immunomodulatory therapies. Citation Format: Arthur Brace, Nathan Sallee, Justin Chou, Lindsay Garrenton, Diana Chen, Ryan Liang, Greg Kemper, David Yang, Marina Jaquez, Janine Powers, Mikayel Mkrtichyan, Thomas Brennan, Luis Borges. Identification of novel T cell co-inhibitory and co-stimulatory receptors from screening a comprehensive library of extracellular proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2633. doi:10.1158/1538-7445.AM2017-2633
Abstract 3968: Canonical NFkB signaling in myeloid cells is required for the glioblastoma growth
Authors: Bhagelu R. Achyut, Jennifer Bradford, Kartik Angara, Mohammad Rashid, Meenu Jain, Thaiz Borin, ASM Iskander, Roxan Ara, Ali Arbab
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM) development and therapeutic resistance has been accompanying with the tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). TAMs are heterogeneous cell populations of immune regulatory myeloid-derived suppressor cells (MDSCs) and polarization of anti-tumor macrophages (M1) into pro-tumor macrophages (M2). We investigated the role of myeloid cell NF-κB signaling in orthotopic GBM model using immune deficient and immune competent hosts. Interestingly, conditional deletion of canonical NF-κB signaling (p65) with Lysm-Cre (p65 KO) in myeloid cells, significantly inhibited syngeneic GL261 tumor growth in immune-competent mice compared to control mice. We studied the TAMs recruitment to the tumor and their polarization under the influence of TME. P65 KO mice displayed decreasing trend of immune cell infiltration (CD45), which phenotyped as decreased F4/80+, CD68+, CD206+ (M2) and Gr1+CD11b+ (MDSCs) macrophages, compared to control mice. This was associated with the increased CD80+ (M1) macrophages, increasing trend of CD4+ and CD8+ cytotoxic T cells, and decreased CD44+ mesenchymal cancer stem cells (CSCs) populations in the TME. Cytokine array data indicated that loss of canonical NF-κB signaling within the TAMs was implicated in increased production of IFNγ, IGF1, MCP1, MIP1α, and TNFα cytokines. Co-culture of T cells with p65 KO or control MDSCs identified increased proliferation of T cells with p65 KO MDSCs compared to control MDSCs. Conversely, GBM patient-derived xenografts and U251 GBM cell line-derived tumors showed increasing trend of growth in immune-deficient mice, following the transplantation of p65 KO bone marrow (BM) compared to control BM. Pro-tumor macrophages and CSCs were increased and T cell populations were decreased in human tumors grown in immune deficient mice transplanted with p65 KO BM, compared with control BM. In addition, analysis of human data set revealed higher expression of p65 subunit of NF-κB complex in brain tumor stroma compared to the tumor cells. The study suggests that canonical NF-κB signaling in TAMs is required for the tumor-promoting macrophage polarization and GBM growth in immunocompetent host compared to immune deficient host. Therefore, targeting myeloid-specific NFκB signaling in GBM could inhibit the immune suppressive TAMs and improve the anti-tumor immunity. Citation Format: Bhagelu R. Achyut, Jennifer Bradford, Kartik Angara, Mohammad Rashid, Meenu Jain, Thaiz Borin, ASM Iskander, Roxan Ara, Ali Arbab. Canonical NFkB signaling in myeloid cells is required for the glioblastoma growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3968. doi:10.1158/1538-7445.AM2017-3968
Abstract 4255: Associations of coffee consumption and caffeine intake with mammographic breast density
Authors: Lusine Yaghjyan, Graham Colditz, Bernard Rosner, Aleksandra Gasparova, Rulla Tamimi
Journal: Cancer Research (2017)

Abstract Purpose: Previous studies suggest that coffee consumption and caffeine intake may be associated with reduced breast cancer risk which may result from stimulating effect of coffee on estrogen metabolism enzymes and subsequent changes in bioavailable estrogen. We investigated the association of coffee consumption and caffeine intake with mammographic density by woman’s menopausal status and, in postmenopausal women, by hormone therapy (HT). Methods: This study included 4,130 cancer-free women within the Nurses’ Health Study and Nurses’ Health Study II cohorts. Percent breast density (PD), absolute dense and non-dense areas were measured from digitized film mammograms using a computer-assisted thresholding technique; all measures were square-root transformed for the analysis to improve normality. Diet was assessed with a food frequency questionnaire; average cumulative coffee/caffeine consumption was calculated using data available from all the questionnaires preceding the mammogram date. Information regarding breast cancer risk factors was obtained from baseline or biennial questionnaires closest to the mammogram date. We used generalized linear regression to quantify associations between exposures and breast density measures, adjusted for potential confounders. Associations were examined separately for regular coffee, decaffeinated coffee, total coffee, and energy-adjusted caffeine intake. Results: In multivariable analyses, decaffeinated coffee was positively associated with PD in premenopausal women (2+ cups/day: β=0.23, p-trend=0.03). In postmenopausal women, decaffeinated and total coffee were inversely associated with PD (decaffeinated coffee 2+ cups/day: β=-0.24, p-trend=0.04; total coffee 4+ cups/day: β=-0.17). These associations appeared to be driven by the inverse associations of these exposures with absolute dense area. Among current HT users (n=980), regular coffee and caffeine intake were inversely associated with PD (regular coffee 4+ cups/day: β=-0.29, p-trend&amp;lt;0.01; caffeine 4th vs. 1st quartile: β=-0.32, p-trend&amp;lt;0.01). Among past users (n=430), decaffeinated coffee was inversely associated with PD (2+ cups/day β=-0.70, p-trend=0.02). Conclusions: Our findings suggest that among current HT users, regular coffee and caffeine are inversely associated with mammographic percent breast density. Citation Format: Lusine Yaghjyan, Graham Colditz, Bernard Rosner, Aleksandra Gasparova, Rulla Tamimi. Associations of coffee consumption and caffeine intake with mammographic breast density [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4255. doi:10.1158/1538-7445.AM2017-4255