tbuckley/cabot-search huggingface dataset:
Abstract 10236: Natural Killer T Cells are Involved in Atherosclerotic Plaque Instability in Apolipoprotein-E Deficient Mice
Authors: Naoki Ishimori, Yoshinori Ohmura, Shunpei Horii, Satoshi Tokuhara, Atsushi Nozawa, Akimichi Saito, Hiroyuki Tsutsui
Journal: Circulation (2010)

Objective: The infiltration and activation of macrophages as well as lymphocytes within atherosclerotic lesion contribute to the pathogenesis of plaque rupture. We have demonstrated that natural killer T (NKT) cells, a unique subset of T lymphocytes which recognize glycolipid antigens and secrete a large amount of TH1/TH2 cytokines on activation, have a crucial role in atherogenesis. However, it remains unclear whether NKT cells are involved also in plaque instability. Methods: Male apolipoprotein E (apoE) deficient mice were fed with a standard diet (SD) or a high-fat diet (HFD) for 8 weeks. The SD- and the HFD-fed mice were divided into 2 groups according to the injection of α-galactosylceramide (αGC, 2μg/body, intraperitoneally twice a week; SD-αGC and HFD-αGC; n=7 and n=21, respectively) that specifically activates NKT cells or phosphate-buffered saline (PBS; SD-PBS and HFD-PBS; n=6 and n=21, respectively). Plaque instability was assessed at the brachiocephalic artery by the histological analysis. The...
Abstract 4717: MAP kinase inhibition induces metabolic reprogramming in T-cells leading to induction of stem cell memory CD8 cells that enhance potency of adoptive cell therapy and anti-OX40 antibody
Authors: Vivek Verma, Shamim Ahmad, Peng Zeng, Mikayel Mkrtichyan, Simon T. Barry, Paul D. Smith, Paulo C. Rodriguez, John E. Janik, Seema Gupta, Samir N. Khleif
Journal: Cancer Research (2018)

Abstract Adoptive T-cell therapy has demonstrated remarkable activity in refractory malignancies; however, the short survival of these cells in some patients results in treatment failure. CD8+ T-cells with self-renewable stem cell memory (TSCM) phenotype persist longer than the effector cells. Hence pharmacologic agents that maintain lymphocytes in TSCM phenotype may benefit the adoptive T cell-transfer strategies as well as combination immunotherapies. Small-molecule inhibitors of mitogen-activated protein kinase (MEKi) have been used for treatment of solid tumors. Here we report that inhibition of MEK enhances immune-driven antitumor response. We show that MEKi prevents the terminal differentiation and exhaustion of CD8+ T-cells in the tumor microenvironment. Interestingly, we further observed that MEKi leads to a significant increase in the CD62LhiCD44loSca1+ cells with low mitochondrial potential that are defined as TSCM CD8+ cells. Furthermore, ex vivo MEKi-treated CD8+ cells demonstrated a significantly higher antitumor activity in tumor-bearing mice. These MEKi treated CD8+ T-cells have higher mitochondrial respiration, which is fueled by fatty acid oxidation and exhibit significantly enhanced spare respiratory capacity (SRC). In addition, MEKi-treated cells have higher metabolic fitness, making them resistant to terminal exhaustion upon cell activation. Since OX40 co-stimulatory signals potentiate the self-renewal and homeostatic capacity of memory T-cells, we treated the tumor-bearing mice with MEKi in combination with OX40 agonistic antibody. Combining MEKi with OX40 agonist antibody significantly enhanced anti-OX40 antitumor effect. These data highlight the ability of pharmacologic MEK inhibition in inducing TSCM, which can be used ex vivo to enhance the potency of T-cell therapies and in vivo in combination immune therapy. Citation Format: Vivek Verma, Shamim Ahmad, Peng Zeng, Mikayel Mkrtichyan, Simon T. Barry, Paul D. Smith, Paulo C. Rodriguez, John E. Janik, Seema Gupta, Samir N. Khleif. MAP kinase inhibition induces metabolic reprogramming in T-cells leading to induction of stem cell memory CD8 cells that enhance potency of adoptive cell therapy and anti-OX40 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4717.
Letter by Niccoli et al Regarding Article, “Intracoronary Versus Intravenous Administration of Abciximab in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention With Thrombus Aspiration: The Comparison of Intracoronary Versus Intravenous Abciximab Administration During Emergency Reperfusion of ST-Segment Elevation Myocardial Infarction (CICERO) Trial”
Authors: GiampaoloNiccoli, NicolaCosentino, FilippoCrea
Journal: Circulation (2011)
Abstract 3660: Can the presence of fusion genes in circulating cell-free DNA serve as potential biomarkers for Ewing's sarcoma
Authors: Shintaro Iwata, Hajime Kageyama, Tsukasa Yonemoto, Makiko Itami
Journal: Cancer Research (2018)

Abstract Background: Circulating cell-free DNA (cfDNA) is fragmented DNA derived from tumors that circulates in the blood of patients. With liquid biopsy, cfDNA has the potential to be used to monitor tumor burden in real time. Most reports have described that tumor-specific alterations in cfDNA are mutations, although little has been reported for the detection of tumor specific gene fusions. The objective of this study was to identify whether cfDNA can be used to detect tumor specific gene fusions and whether this would reflect the tumor burden of patients with Ewing's sarcoma. Patients and Methods: Multiplex long-range genomic PCR was performed to detect patient-specific genomic breakpoints in eight patients. Probes for digital PCR were designed based on the genomic breakpoint of each patient. cfDNA was extracted from the serum of patients, which was drawn at multiple time-points (pretreatment, completion of the treatment, and/or relapse). cfDNA quantification was performed by digital PCR (BioRad Qx-200). Results: Gene fusions in the cfDNA were detected in six (75%) of eight patients with high specificity. The relative gene fusion copy ratio (gene fusion copy number/wild KRAS copy number) was higher in the patients with M1b (extrapulmonary metastases at diagnosis) compared to the patients with M1a (pulmonary metastases at diagnosis) or M0 (no metastasis), although no significant relationship was observed between the relative gene fusion copy ratio and chemosensitivity. In each patient, the relative gene fusion copy ratio was the highest in pretreatment samples and decreased as the treatment progressed. Patients with relapse displayed an elevated relative gene fusion copy ratio in advance of clinical manifestation or elevation of lactase dehydrogenase. Conclusion: The amount of cfDNA in the serum strongly correlated with the treatment stage and would be useful as an early biomarker for Ewing's sarcoma patients. Citation Format: Shintaro Iwata, Hajime Kageyama, Tsukasa Yonemoto, Makiko Itami. Can the presence of fusion genes in circulating cell-free DNA serve as potential biomarkers for Ewing's sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3660.
Abstract 1455: FAK overexpression upregulates glucose metabolism in glioblastoma
Authors: Kiran Kumar Velpula, Michael Pajor, Maheedhara R. Guda, Collin M. Labak, Simon Park, Andrew J. Tsung
Journal: Cancer Research (2018)

Abstract Glioblastoma (GBM) is the most aggressive brain cancer, afflicting nearly 1 in 6 adult patients with brain tumors. Currently, no effective curative treatment for this CNS neoplasm exists. The high prevalence and dismal prognosis of GBM increases the need to identify novel therapeutic targets. Previous research has suggested that increased expression of focal adhesion kinase (FAK) may play a role in tumor metabolism. Our preliminary data using datamining approach of the TCGA and Oncomine™ databases showed that mRNA levels of FAK correlate with expression levels of the glucose transporter GLUT1. Subsequent mass-spectrometric and immunoprecipitation experiments provided evidence that FAK binds to GLUT1, while immunohistochemistry and immunocytochemistry experiments confirmed their interaction. Western blot analysis using shRNA to silence FAK demonstrated a significant decrease in GLUT1 expression. Cells treated with the same FAK shRNA showed decreased metabolites from anaerobic glycolysis, instead relying on oxygen-dependent metabolism utilizing oxidative phosphorylation for their energy supply. Collectively, we propose that FAK is a viable target in modulating glucose uptake and metabolism in GBM. Citation Format: Kiran Kumar Velpula, Michael Pajor, Maheedhara R. Guda, Collin M. Labak, Simon Park, Andrew J. Tsung. FAK overexpression upregulates glucose metabolism in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1455.
Abstract 119: Immunotherapy with dendritic cells inhibited tumor growth on an ID8 orthotropic mouse model of ovarian cancer
Authors: Min-Je Kim, Joo-won Kim, Ju-hyun Kim, Young-Jae Lee, Shin-Wha Lee, Yong-Man Kim
Journal: Cancer Research (2018)

Abstract Background and Purpose: Ovarian cancer is the most frequent cause of death from gynecologic malignancy. Recently, immunotherapies have been suggested as ways to treat this malignancy. However, the ideal of immunotherapy has not been realized yet in ovarian cancer patients. Therefore, we investigated effects of monocyte-derived dendritic cells (mono DCs) and new-generation DCs subset (new DCs) on an ID8 orthotropic mouse model of ovarian cancer. Methods: Mono DCs were prepared from bone marrow of C57BL/6 mice. We isolated monocyte from bone marrow by monocyte isolation kit. Isolated monocyte was incubated for 7 days with IL-4 and GM-CSF. In addition, monocytes were pulsed with LPS and ID8 tumor lysate while incubating. Likewise new DCs were isolated from bone marrow of C57BL/6 mice. We isolated lineage negative cells from bone marrow using lineage cell depletion kit. Isolated cells were incubated with IL-4 and GM-CSF; also the cells were pulsed by ID8 tumor lysate and Rg3, which is a ginsenoside. Orthotropic model of ID8 was made on C57BL/6 mice. We injected 5x106 cells into peritoneal cavity. 4 weeks after cell injection, mice were grouped into three groups, which were vehicle, mono DCs and new DCs. Mice were injected with mono DCs and new DCs. 5x106 cells of DCs were injected 1 time/week for three weeks. One week later, mice were sacrificed and organs were harvested such as peritoneum, phren, ovary and tumor mass for histologic analysis. Results: DCs treated groups showed lower ascites formation than vehicle group. Ascites were fewest in new DCs group. Survival rate was lowest in vehicle group. Each survival rate is 0% in vehicle, 63% in new DCs and 80% in mono DCs. Also tumor growth at ovary was more decreased in mono DCs and new DCs group. In addition, mono DCs-treated mice showed low level of metastasis to other organs. Conclusion: Immunotherapy with dendritic cells showed inhibition of tumor growth and metastasis on mouse ovarian cancer. These results indicated that DCs treatments are able to be a potential therapy for ovarian cancer. It also could have synergy with the combined treatment of existing anticancer drugs. However, there are several limitations such as a relatively high dose of DCs and the procedure of isolating DCs needed large amount of bone marrow. We will continue to study and improve these issues. Citation Format: Min-Je Kim, Joo-won Kim, Ju-hyun Kim, Young-Jae Lee, Shin-Wha Lee, Yong-Man Kim. Immunotherapy with dendritic cells inhibited tumor growth on an ID8 orthotropic mouse model of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 119.
Abstract 14323: Long-term Outcomes of Acute Coronary Syndrome Patients With High Serum D-dimer Level
Authors: Chisato Sato, Kohei Wakabayashi, Takahiro Furuya, Tenzeen Nishikura, Naoko Ikeda, Miwa Kikuchi, Fumiyoshi Miyoshi, Tsutomu Toshida, Hiroshi Suzuki, Kaoru Tanno
Journal: Circulation (2016)

Introduction: D-dimer (DD) is a fibrin degradation product, and the blood test helps diagnosis of thrombosis. The serum DD level may indicate a large thrombus within coronary artery in acute coronary syndrome (ACS) patients. The impact of serum DD level on clinical outcomes is still unclear in those patients. Hypothesis: High serum DD level is associated with low final TIMI flow grade and poor long-term outcomes in ACS patients. Methods: A total of 561 consecutive ACS patients who admitted to Showa University Fujigaoka Hospital from 2011 to 2015 were studied. The patients were divided into two groups according to serum DD level on admission: high DD group (≧1.0 μg/ml, n = 246) and low DD group (<1.0 μg/ml, n = 315). Primary end point was long-term mortality. Secondary end point was final TIMI flow grade after percutaneous coronary intervention and major adverse cardiac and cerebrovascular events (MACCE). Results: High DD group was older than low DD group [71.8 ± 12.3 vs. 64.9 ± 12.6, p < 0.001]. Gender an...
Abstract B23: The evolution of estrogen receptor signaling in the progression of endometriosis to endometriosis-associated ovarian cancer
Authors: Michelle Boisen, Courtney Andersen, Matt Sikora, Tianzhou Ma, George Tseng, Anda Vlad, Esther Elishaev, Uma Chandran, Robert Edwards, Steffi Oesterreich
Journal: Clinical Cancer Research (2018)

Abstract Objectives: To investigate changes in estrogen receptor–alpha (ERα) signaling during the progression of endometriosis to endometriosis-associated ovarian cancer (EAOC) as a putative driver of malignant transformation. Methods: We procured tissue samples of normal endometrium (n=23), endometriosis (benign, n=19; atypical, n=11; concurrent with EAOC, n=9), and EAOC (n=21). In this cohort, we evaluated expression of a 236-gene signature of estrogen signaling. ANOVA and unsupervised clustering were used to identify distinct gene expression profiles across disease states. These profiles were compared to public profiles of estrogen regulation in preclinical cancer models from the Gene Expression Omnibus (GEO). Gene set enrichment analysis (GSEA) was performed to determine whether gene expression in EAOC was consistent with ERα activity. Results: ANOVA revealed 158 differentially expressed genes (q&amp;lt;0.05) and unsupervised clustering identified 4 distinct gene clusters. Cluster 1 comprises genes with increasing expression from benign endometriosis to EAOC (e.g. FGF18, ESR2). Clusters 2 and 3 include genes that are overexpressed or downregulated in EAOC compared to benign endometriosis, respectively (e.g., NRIP1, IGFBP3). Cluster 4 consists of genes with an incremental decrease in expression from benign endometriosis to EAOC (e.g., ESR1, PGR, and GREB1). The estrogen signaling profile of EAOC was not consistent with activated ERα in the preclinical models. Further, GSEA did not identify signatures of activated ERα in EAOC but instead identified expression patterns consistent with loss of ERα function and development of endocrine resistance. Conclusions: Gene expression data suggest that classical ERα signaling becomes inactivated throughout the progression of endometriosis to EAOC. Rather, the gene expression pattern in EAOC is more consistent with profiles of endocrine resistance. De-repression of ERα target genes such as FGF18 may contribute to evolution of endometriosis into EAOC. Citation Format: Michelle Boisen, Courtney Andersen, Matt Sikora, Tianzhou Ma, George Tseng, Anda Vlad, Esther Elishaev, Uma Chandran, Robert Edwards, Steffi Oesterreich. The evolution of estrogen receptor signaling in the progression of endometriosis to endometriosis-associated ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B23.
Abstract 4300: Cell cycle pathway gene regulation in glioblastoma multiforme (GBM) and GBM derived stem cells: Implicating Pentraxin 3 upregulation
Authors: Umadevi V. Wesley, Paul Clark, Jacob Jaeger, John Kuo, Robert Dempsey
Journal: Cancer Research (2018)

Abstract Introduction: Glioblastoma Multiforme (GBM) is the most aggressive type of brain cancer and progresses at a rapid rate. The major obstacle in the treatment of GBM is selective survival of a subpopulation of GBM derived stem cells (GSC) which are highly proliferative and resistant to drug induced apoptosis. The proteins involved in the regulation of the cell cycle impact survival potential of GBM and GSCs. Pentraxin 3 (PTX3), an angiogenic and survival factor plays a key role in cell proliferation, angiogenesis and invasion. However, little is known about the association of PTX3 and cell cycle regulation in GBM derived stem cells. Mehods: GBM patient tumor lines, and GSC derived from the same GBM lines were used. These cell lines were exposed to hypoxia and re-oxygenation. Cell cycle profiling and analysis were carried out using flow cytometry and FlowJo Single Cell Data Analysis Software. Xeno-transplanted mouse brain sections were used for PTX3 expression analysis by immunohistochemistry and immunofluorescence staining. Targeted proteomic approach was used to determine PTX3 levels in GBM and GSC. Alterations in the cell cycle regulatory gene expression in GSC and GBM tumor line in presence and absence of PTX3 was identified by transcriptome array analysis. Results: Our targeted proteomic approach using antibody array identified substantially higher levels of PTX3 in GSCs. GBM tumor lines showed higher percent of cells in G1 phase, where as GSCs showed increased number of cells in G2 and S-phase, both under normoxia and hypoxia. GSCs showed increased levels of GADD45A, known to protect GBM cells from apoptosis. Increased PTX3 expression correlated with increased cell cycle progression. Furthermore, exogenous PTX3 increased CyclinD1, a protein required for progression through the G1 phase of the cell cycle. Conclusion: GSC cells show cell cycle progression, presumably with an increased growth advantage. PTX3 expression is associated with GBM malignancy, and may contribute to GBM cell cycle progression and invasion. Overall, these results indicate that PTX3 and the cell cycle pathway are strongly associated with malignant GBM. Citation Format: Umadevi V. Wesley, Paul Clark, Jacob Jaeger, John Kuo, Robert Dempsey. Cell cycle pathway gene regulation in glioblastoma multiforme (GBM) and GBM derived stem cells: Implicating Pentraxin 3 upregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4300.
Abstract 5298: The accurate noninvasive staging of liver fibrosis using deep learning radiomics: A prospective multicenter study
Authors: Hui Zhou, Kun Wang, Jie Tian
Journal: Cancer Research (2018)

Abstract Purpose: We developed the deep learning Radiomics of elastography (DLRE) as a noninvasive method to assess liver fibrosis stages,which is essential for prognosis, surveillance of chronic hepatitis B (CHB) patients. Methods and Materials: 402 patients were prospectively enrolled from 12 hospitals, and finally 2010 images were included into analysis randomly.DLRE adopted the CNN method, one of the deep learning radiomic techniques, for the automatic analysis of 2D-SWE images. This study was conducted to assess the accuracy of DLRE in comparison with 2D-SWE, transient elastography (TE), transaminase-to-platelet ratio index (APRI), and fibrosis index based on the four factors (FIB-4), by using liver biopsy as the gold standard. Analysis of receiver operating characteristic (ROC) curve were performed to calculate optimal area under it (AUC) for cirrhosis (F4), advanced fibrosis (≥F3), and significance fibrosis (≥F2) for all diagnostic approaches. Results: AUCs of DLRE were both 0.98 for cirrhosis (95% confidence interval [CI]: 0.95-0.99) and advanced fibrosis (95% CI: 0.94-0.99), which were significantly better than other methods, as well as 0.76 (95% CI: 0.72-0.81) for significance fibrosis (significantly better than APRI and FIB-4). Conclusion: DLRE shows the best overall performance in predicting liver fibrosis stages comparing with 2D-SWE, TE, and serological examinations. It is valuable and practical for popularized application of noninvasive diagnosis of liver fibrosis stages in HBV infected patients. Citation Format: Hui Zhou, Kun Wang, Jie Tian. The accurate noninvasive staging of liver fibrosis using deep learning radiomics: A prospective multicenter study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5298.
Abstract 4365: Targeting the RhoA guanine nucleotide-exchange factor Syx for the treatment of glioblastoma
Authors: Wan-Hsin Lin, Ryan Feathers, Laura Lewis-Tuffin, Panos Anastasiadis
Journal: Cancer Research (2018)

Abstract The RhoA GTPase is thought to play a crucial role in cancer development. Its activation is tightly controlled by numerous guanine nucleotide-exchange factors (GEFs). We previously showed that Syx, a RhoA-GEF, promotes junctional integrity in endothelial cells and governs cell polarity and directed migration in glioblastoma (GBM) cells. GBM is a grade IV glioma with a median survival of approximately 14 months. Importantly, the gene locus of Syx (Plekhg5) is located within chromosome 1p36, a region deleted in oligodendroglioma (a type II/III glioma) and associated with better prognosis, suggesting a role of Syx in GBM aggressiveness. Here we show that Syx is a potential target for the treatment of GBM. Knockdown of Syx resulted in altered expression of cell cycle regulators, including cyclins A, B, and E, cyclin-dependent kinase inhibitors (CDIs), namely p21 and p27, and mitosis modulators CDC20 and survivin. These defects resulted in G2/M arrest and dysfunction of cell division, leading to improper chromosome segregation and DNA double-strand breaks. However, DNA damage response could not be activated effectively for DNA repair, leading to cellular apoptosis. Consistent with these findings, we used an orthotopic patient-derived xenograft GBM model to show that Syx silencing results in decreased tumor growth accompanied by increased animal survival. Agents that cause DNA damage and/or disruption of DNA repair pathways are often used for cancer therapy. We thus tested the possibility of targeting Syx for GBM treatment, and showed that Syx knockdown in combination with temozolomide, a first-line drug for GBM, synergistically inhibit cell growth. In summary, this is the first study showing the role of Syx in GBM cell growth and that targeting this signaling pathway can be beneficial for GBM therapy. Citation Format: Wan-Hsin Lin, Ryan Feathers, Laura Lewis-Tuffin, Panos Anastasiadis. Targeting the RhoA guanine nucleotide-exchange factor Syx for the treatment of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4365.
Physicochemical, pharmacokinetic and pharmacodynamic analyses of amphiphilic cyclodextrin-based nanoparticles designed to enhance intestinal delivery of insulin
Authors: Elena Presas, Fiona McCartney, Eric Sultan, Corina Hunger, Sabine Nellen, Clara V. Alvarez, Ulrich Werner, Didier Bazile, David J. Brayden, Caitriona M. O'Driscoll
Journal: Journal of Controlled Release (2018)