tbuckley/cabot-search huggingface dataset:
Abstract 5547: A computational approach to predict tissue level cell cycle regulatory network for normal proliferating and cancer cells
Authors: Tao Sheng, Sha Cao, Chi Zhang, Ying Xu
Journal: Cancer Research (2017)

Abstract Cell cycle control and regulation has been widely studied in terms of cyclin-dependent kinases (CDKs) activities, while only limited information are available on tissue contexts and signaling. In this study, we adopted a systems biology approach aiming to comprehensively capture how tissue level signaling events orchestrate cell cycle phases in a CDKs activities independent manner in both of normal and tumor tissues. We have applied our in house gene co-expression and bi-clustering analysis on a collection of 8 single cell transcriptomic sequencing datasets of normal proliferating human embryonic cells, 17 RNA-seq transcriptomic datasets of inflammatory tissues and 30 microarray data sets of chronic inflammatory diseases as normal proliferating reference and TCGA RNA-seq data for 20 cancer types aiming to identify cell cycle associated gene co-expression modules. Our results suggest that the tissue level signaling events are generally show distinct regulatory structures between tumor and normal tissues: 1) the Rho GTPase signaling pathways that control cell polarity, activate in G2/M transition phase in normal tissue, while mainly in G1 and S phases in tumor. 2) Focal adhesion kinases (FAK) drives G1/S transition in normal tissues, while activated in multiple phases in tumor. 3) Hippo signaling for cell size control activates at G2/M transition phase in normal tissue while in multiple phases in tumor. In addition, we have also generated tissue level regulatory networks for cell cycle controls by predicting possible collective effects of extra- and intra-cellular signaling for both normal proliferating and cancer cells. Citation Format: Tao Sheng, Sha Cao, Chi Zhang, Ying Xu. A computational approach to predict tissue level cell cycle regulatory network for normal proliferating and cancer cells [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 5547. doi:10.1158/1538-7445.AM2017-5547
Abstract 1496: Connecting the metallome with metabolism in ovarian cancer
Authors: Eric D. Shide, Lauren Amable
Journal: Cancer Research (2017)

Abstract Ovarian cancer has historically been diagnosed late stage and lacks effective biomarkers for detection and prognosis. The deregulation of metabolism and signaling cascades inherent of cancer may contribute to aberrant levels of metal within cells. Biological processes essential for cell proliferation require metals for enzyme cofactors, signaling molecules, and structural components. Metallomics is the study of the comprehensive, dynamic metal profile within cells. The goal of our study was to characterize the ovarian cancer metallome at the level of whole cell and mitochondria in comparison to non-cancer. Additionally, cellular metabolism was analyzed to connect the mitochondrial (mito-)metallome to mitochondrial function. Ten human ovarian cancer cell lines were used for experiments: A2780, CAOV3, A2780/CIS, A2780/CP70, ES2, OVCAR3, OVCAR5, SKOV3, TOV112, and TOV21. Three non-cancer human ovarian cell lines of epithelial and fibroblast origin served as controls. Inductively coupled mass spectrometry (ICP-MS) was used to evaluate the metallome by measuring the following metals: calcium (Ca), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), molybdenum (Mo), phosphorous (P), sulfur (S), selenium (Se), and zinc (Zn). An XF24 Seahorse analyzer was used to measure cellular metabolism and mitochondrial function in the ovarian cancer and non-cancer cell lines. Our results demonstrated that there was a distinct metal profile at the level of the whole cell and mitochondria in ovarian cancer cells compared to non-cancer ovarian cells. The whole cell ovarian cancer metallome consisted of increased Mg, P, and Cu, and decreased Fe, Mn, and Se in comparison to non-cancer. The cancer mito-metallome consisted of increased Mg, P, Cu, Zn, Se, and Ca. Referencing established literature of the known metals that serve as cofactors for mitochondrial proteins, the relationship between the mito-metallome and functional metabolic pathways was established. Changes in cellular metabolism were reflected by changes in the mito-metallome. Our study was the first to evaluate an extensive panel of metals simultaneously in the mitochondria and bridge the unique metal signature of ovarian cancer to cell metabolism. Future proteomics studies will be used to further validate the connection of metals to cellular function. Metallomics and the ovarian cancer cell metallome provide further understanding of how cancer deregulates the metallome and how metallomics may provide an avenue for identifying new cancer biomarkers and allow for effective targeting of cancer with chemotherapy. Citation Format: Eric D. Shide, Lauren Amable. Connecting the metallome with metabolism in ovarian cancer [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 1496. doi:10.1158/1538-7445.AM2017-1496
Abstract 5433: β-Tubulin inhibitors reduce GLUT1 membrane trafficking to attenuate tumorigenesis in glioblastoma subtypes
Authors: Collin M. Labak, Maheedhara R. Guda, Swapna Asuthkar, Neha Jain, Yining Lu, Ian Purvis, Jack Tuszynski, Ichiro Nakano, Andrew J. Tsung, Kiran K. Velpula
Journal: Cancer Research (2017)

Abstract Glioblastoma is an aggressive, high-grade tumor with poor prognosis due to lack of sound therapeutic options. Mesenchymal subtype GBMs are particularly difficult to treat because they tend to proliferate in the sub ventricular zone, an area that breeds stem-like neural cells and proves nearly impossible to access for surgical resection. They also contribute to creating a hypoxic microenvironment and switch to glycolytic metabolism in what is known as the Warburg Effect. Here, we hypothesize that strategically inhibiting the glucose transporter, GLUT1, through cytoskeletal components that traffic it to the cell membrane may reverse the Warburg Effect, attenuating further tumorigenesis and decreasing the stemness of such cells. Datamining studies and immunoblot analysis conducted on human glioblastoma patient specimens (hGBM) demonstrated that GLUT1 is highly upregulated. Limiting dilution assay conducted using GLUT1 inhibitors- fasentin and 2-Deoxy-D-glucose reduced the proliferation in mesenchymal cancer stem cell (CSC) subtype in in vitro culture. Simultaneously, mass spectrometric analysis revealed significant association between GLUT1 and β-tubulin 4 (TUBB4) in mesenchymal subtyped cells. This association was further confirmed by large-sample datamining and in immunoprecipitation studies from hGBM specimens, suggesting that TUBB4 may be a viable target in deterring the trafficking of upregulated GLUT1 to the membrane. Collectively, these studies confirm that GLUT1 is associated with TUBB4, and that targeting TUBB4 via siRNA or colchicine derivatives could prove effective in reversing the Warburg Effect in GBM cells and ultimately improve patient outcomes. Citation Format: Collin M. Labak, Maheedhara R. Guda, Swapna Asuthkar, Neha Jain, Yining Lu, Ian Purvis, Jack Tuszynski, Ichiro Nakano, Andrew J. Tsung, Kiran K. Velpula. β-Tubulin inhibitors reduce GLUT1 membrane trafficking to attenuate tumorigenesis in glioblastoma subtypes [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 5433. doi:10.1158/1538-7445.AM2017-5433
Abstract 3099: pH-regulated hydrophilicity/hydrophobicity-, surface charge-reversible and redox sensitive nanogels for anticancer drug delivery
Authors: Hao Yang, Qin Wang, Fuying Li, Yanhong Zhu, Lu Gan, Xiangliang Yang
Journal: Cancer Research (2017)

Abstract Long circulation in blood, enhanced tumor accumulation and penetration, efficient cellular internalization and intracellular drug release are major challenges in the development of ideal anticancer drug delivery systems. Although several strategies have been reported to improve therapeutic efficacy, they mainly meet one or a few features which can not circumvent all the barriers. Here the stimuli-responsive zwitterionic nanogels were developed to overcome the sequential physiological barriers in cancer chemotherapy. The nanogels were constructed via a simple precipitation polymerization method by using temperature-sensitive monomer N-isopropylacrylamide (NIPAM) pH-responsive monomer methylallyl amine (MAA) and betaine-based zwitterionic monomer sulfobetaine methacrylate (SBMA) with in vivo anti-protein adsorption property as comonomers, and disulfide bonds-containing N, N'-bis(acryloyl) cystamine (BAC) as crosslinker. Volume phase transition temperature (VPTT) and surface charge of the prepared nanogels were precisely controlled by altering the feeding molar ratio of these comonomers. Remarkably, The nanogels possess ultra-pH sensitive hydrophilicity/hydrophobicity reversible property, in which the nanogels were hydrophilic in the blood (pH 7.4, 37 °C) for prolonged circulation, while they were rapidly switched to hydrophobic with similar size and surface charge at acidic tumor pH, resulting in enhanced tumor accumulation and penetration and strong internalization by normal cancer cells and CSCs. For efficient lysosomal escape and intracellular drug release, the nanogels were positively charged at lysosome pH, which allowed them to be transported into the cytosol where the loaded cargo DOX was released from the nanogels with the introduction of intracellular high GSH concentration to exert cytotoxicity. This study indicated that pH-dependent hydrophilicity/hydrophobicity-, surface charge-reversible and redox sensitive nanogels might be used as potential carriers for anticancer drugs, which provided a foundation for designing an effective drug delivery system for cancer therapy. Note: This abstract was not presented at the meeting. Citation Format: Hao Yang, Qin Wang, Fuying Li, Yanhong Zhu, Lu Gan, Xiangliang Yang. pH-regulated hydrophilicity/hydrophobicity-, surface charge-reversible and redox sensitive nanogels for anticancer drug delivery [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 3099. doi:10.1158/1538-7445.AM2017-3099
Abstract 5893: Bioenergetic signature from cocultures of pancreatic tumor cell lines and fibroblasts
Authors: Mª Teresa Agulló-Ortuño, Elena Prieto-García, C. Vanesa Díaz-García, Irene Otero Blas, Inmaculada García-Ruíz, José A. López-Martín
Journal: Cancer Research (2017)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the tumors with greater invasiveness and metastasis. PDAC is associated with a large desmoplastic reaction, characterized by fibroblastic proliferation and extracellular matrix secretion. Besides, cellular bioenergetics has become a central issue of investigation in cancer biology, because the altered energy metabolism of cancer cells has been proposed as a potential target for cancer treatment. We have established co-cultures between PDAC cell lines (Capan-1 or PL-45) and fibroblasts (LC5). A reverse phase protein microarray (RPMA) approach has been applied to quantify proteins of energy metabolism in theses co-cultures, with the aim of identifying potential biomarkers in PDACs. The fifteen proteins of energy metabolism studied included members of the mitochondrial oxidation of pyruvate, the tricarboxylic acid cycle, β-oxidation of fatty acids, electron transport and oxidative phosphorylation, glycogen metabolism, glycolysis and oxidative stress using highly specific antibodies. Co-cultures modified proteins expression of energy metabolism, respect to monocultures. Capan-1 in co-culture increased several proteins belonging to OXPHOS (NDUFS3, SDHB, CORE2 and COXII), the antioxidant SOD2, the mitochondrial HSP60, and G6PDH. The expression of the glycolitic PKM2 decreased. Their fibroblasts partners increased the expression of SDHB and also decreased PKM2. PL-45 in co-culture, experimented an increase in HADHA. Their fibroblasts partners showed a decrease in PKM2, LDHA, IF1, PDHe and HSP60.Capann-1 and PL-45 in co-culture with fibroblast, differ en their energy metabolism phenotype. Overall, the results indicate that the quantification of bioenergetic signature offers potential biomarkers that could be implemented to refine the understanding of the biological principles of PDAC and, eventually, the management of patients with these tumors. Citation Format: Mª Teresa Agulló-Ortuño, Elena Prieto-García, C. Vanesa Díaz-García, Irene Otero Blas, Inmaculada García-Ruíz, José A. López-Martín. Bioenergetic signature from cocultures of pancreatic tumor cell lines and 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 5893. doi:10.1158/1538-7445.AM2017-5893
Abstract 4754: Fractionated whole brain radiation-induced behavioral changes in athymic nude mice is associated with sustained neuroinflammation and microglial M1-phenotype
Authors: Suman Kanji, Benjamin Johnson, Kristina Witcher, Pooja Gulati Gulati, Shannon Chen, Jonathan Godbout, Randy J. Nelson, Saikh Haque, Arnab Chakravarti
Journal: Cancer Research (2017)

Abstract The objective of this study is to study the late-chronic effects of fractionated whole brain irradiation (fWBI) on cognitive impairment and associated cellular and molecular neuro-inflammatory mechanisms using clinically relevant and reliable mouse models. Microglia are recognized as the primary innate immune component of neuroinflammation. However, microglial contributions to radiation-induced cognitive impairment are poorly understood. Here, an athymic nude (Nu/Nu) mouse model was employed to address this issue. Mice were divided into two groups: radiation treatment (XRT) and no-treatment control (CTL). The whole brain of each XRT mouse received 30 Gy (3 Gy/fraction) of radiation over two weeks. XRT and CTL mice were assessed for cognitive and behavioral changes at 1, 4, and 6 months posttreatment using the novel object recognition test (for long-term, non-spatial memory), the free running Y-Maze (for short-term, spatial memory) and Barnes Maze (for spatial learning and memory). A significant decline in novel object recognition in the XRT group (P&amp;lt;0.05) was seen at the 4 month time point and continued to persist at 6 months (P&amp;lt;0.05). No significant changes in the Barnes maze or Y-maze were seen at these time points. Expression of neuroinflammatory mediator genes, from both whole brain and isolated microglia, were measured by RT-PCR. We found that markers of the M1-phenotype, which include TNF-α, and MHC II, were significantly upregulated (P&amp;lt;0.05) and markers of the general M2 Phenotype, which include IL-4ra, IL-10ra, and TGF-β, were downregulated (P&amp;lt;0.05) at 1 and 6 month time points. These results indicate that sustained neuroinflammation and microglial M1-polarization are associated with long-term cognitive impairment induced by fWBI. Radiotherapy is the most prevalent treatment for primary and metastatic brain tumors. Whereas previous studies that identified important mechanisms underlying XRT-induced cognitive decline had used treatment regimens that were not clinically relevant ones, we have employed a clinically relevant fractionation scheme to address the cellular and molecular deregulations in association with cognitive impairment. Citation Format: Suman Kanji, Benjamin Johnson, Kristina Witcher, Pooja Gulati Gulati, Shannon Chen, Jonathan Godbout, Randy J. Nelson, Saikh Haque, Arnab Chakravarti. Fractionated whole brain radiation-induced behavioral changes in athymic nude mice is associated with sustained neuroinflammation and microglial M1-phenotype [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 4754. doi:10.1158/1538-7445.AM2017-4754
Abstract LB-071: A facile strategy for exosome labeling and tracking
Authors: Young Kim, Tae-Sup Lee, Ching H. Tung
Journal: Cancer Research (2017)

Abstract Exosomes are extracellular vesicles of endocytic origin with a size range of 40-150 nm and a lipid bilayer membrane. Though exosomes are known as dynamic mediators of intercellular communication, its characteristics and function have not been fully studied. In this report, we used a metabolic labeling method to prepare fluorescent exosomes to investigate the characteristics and the movement of exosomes derived from various breast cancer cells. MCF-7 and MDA-MB-231 cells were treated with three types of azido sugars, Ac4ManNAz, Ac4GalNAz, or Ac4GlcNAz (50 μM), for 3 days to produce the azide (-N3) containing exosomes through metabolic glycosylation. It is confirmed that the azido sugar decorated exosomes were able to maintain their original characteristics such as size, lipid bilayer morphology, and protein profile. The collected exosomes were labeled with Adibo-cy3 and Adibo-cy5.5 fluorescence dyes using copper-free click chemistry. The exosomes prepared with Ac4ManNAz have shown the highest labeling efficiency, in MCF-7 and MDA-MB-231 cells at 17.2% and 14.8%, respectively. To study their homing capability, the labeled exosomes from different origins were incubated with a panel of breast cancer cells, including MCF-7, MDA-MB-231, MDA-MB-468 and BT-549, and normal NIH/3T3 fibroblast cells for 24 hours. The cells were then evaluated by fluorescence microscopic imaging and flow cytometry. It was observed that exosomes from different origins have a different homing efficiency, suggesting that each exosome may have its unique navigation systems. Furthermore, the cells which have aggressive metastatic potential, such as MDA-MB-231, showed a higher uptake in all exosomes. Our development has demonstrated an effective labeling method that facilitates exosome research by providing a new way of quantification and tracking in vitro and potentially in vivo studies. Citation Format: Young Kim, Tae-Sup Lee, Ching H. Tung. A facile strategy for exosome labeling and tracking [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 LB-071. doi:10.1158/1538-7445.AM2017-LB-071
Abstract 766: Comorbidities limiting recruitment of non-small cell lung cancer (NSCLC) patients in early phase trials
Authors: Narjust Duma, Yucai Wang, Aaron Mansfield
Journal: Cancer Research (2017)

Abstract Background: Early phase trials (EPCT) provide significant value by evaluating the possible benefits of new agents. The eligibility criteria in EPCT are usually rigorous and may exclude many patients (pts) commonly seen in clinical practice. Our objective was to identify the most common comorbidities excluded in EPCT for NSCLC. Methods: ClinicalTrials.gov was queried on August 1st of 2016. 299 interventional drug trials were extracted from 2010 to 2016. We studied the trial characteristics including: experimental therapy, location, funding and eligibility criteria. Exclusion of CNS metastasis was treated as a binary variable (strict exclusion vs. allowed). Logistic regressions were used for statistical analysis. Results: Of the 299 trials, 164 (55%) were phase II, 81 (27%) phase I and 54 (18%) phase Ib/II. 164 (55%) were conducted in the United States (US), 45 (15%) in Asia, 39 (13%) in Europe and 51 (17%) were international. 171 (57%) trials were funded by the industry, 54 (18%) by government agencies and 74 (25%) were investigator initiated. Survival was an end-point in 97 (32%) trials. 70 (23%) trials required a repeat lung biopsy. 54 (18%) trials excluded pts &amp;gt;75 years of age. 99 (33%) trials required creatinine levels &amp;lt;1.5 mg/dl, 132 (44%) liver enzymes &amp;lt;2.5 and total bilirubin &amp;lt;1.5 of the upper limit of normal. 88 (29%) trials required Hgb&amp;gt;9 g/dl and 141 (47%) excluded pts with platelets &amp;lt;100,000/dl. In terms of comorbidities, 84 (28%) trials excluded pts with atrial fibrillation, 94 (31%) with any anticoagulation therapy and 120 (40%) HIV positive pts. CNS involvement was a significant exclusion factor, 123 (41%) trials excluded pts with CNS metastasis. On univariate analysis, the odds of CNS metastasis exclusion were significantly higher in immunotherapy trials (OR 1.72, 95%CI 1.2-2.4, p&amp;lt;0.01) and lower in European trials (OR 0.76, 95%CI 0.6-0.9, p&amp;lt;0.005). In multivariate analysis, US based trials had higher odds of exclusion of CNS metastasis (OR: 3.2, 95%CI 1.4-7.5, p&amp;lt;0.05). Conclusions: Many of the EPCTs excluded pts with advanced age, cytopenias and other common comorbidities, eliminating the possibility of many of our aging pts from participation. Regarding CNS disease, our analysis suggests the type of agent and location may influence the trial design about CNS metastasis inclusion. Investigators should review whether sufficient justification exists for every exclusion criterion before their incorporation in future trial protocols. Citation Format: Narjust Duma, Yucai Wang, Aaron Mansfield. Comorbidities limiting recruitment of non-small cell lung cancer (NSCLC) patients in early phase trials [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 766. doi:10.1158/1538-7445.AM2017-766
Next Generation Veto Cells for Non-Myeloablative Haploidentical HSCT: Combining Anti-Viral and Graft Facilitating Activity
Authors: Esther Bachar Lustig, Noga Or Geva, Assaf Lask, Rotem Gidron, Sivan Kagan, Aloukick Kumar Sinqh, Yair Reisner
Journal: Blood (2016)
Coupling Growth Arrest and Adipocyte Differentiation
Authors: Gerard Ailhaud, Christian Dani, Ez-Zoubir Amri, Philippe Djian, Christian Vannier, Alain Doglio, Claude Forest, Danielle Gaillard, Raymond Negrel, Paul Grimaldi
Journal: Environmental Health Perspectives (1989)

The complete differentiation program of preadipose cells can be divided into early and late events. The expression of early markers takes place at growth arrest (G1/S boundary), whereas that of late markers, leading to terminal differentiation, takes place after a limited number of mitoses of early marker-containing cells. Only terminal differentiation requires the presence of growth hormone and triiodothyronine and results in the formation of triacylglycerol-filled, nondividing cells. The events of adipose cell differentiation which take place in vitro allow a better understanding of the development of adipose tissue in vivo.