tbuckley/cabot-search huggingface dataset:
Abstract 1997: Charting the DNA methylation landscape of prostate cancer associated fibroblasts
Authors: Mitchell G. Lawrence, Ruth Pidsley, Elena Zotenko, Birunthi Niranjan, Aaron Statham, Jenny Song, Nicola Armstrong, John Pedersen, Mark Frydenberg, Renea Taylor, Clare Stirzaker, Gail Risbridger, Susan Clark
Journal: Cancer Research (2017)

Abstract Most studies of the genome and epigenome landscape of tumors focus on the aberrations in epithelial cancer cells. However, the growth and progression of solid tumors involves dynamic cross-talk between cancer epithelium and the surrounding microenvironment, including cancer-associated fibroblasts (CAFs). The molecular landscape of these cells is still poorly understood, so it is important to define the epigenetic features that underpin the functional differences between CAFs and non-malignant prostate fibroblasts (NPFs) and influence cancer progression. Therefore, we used whole-genome bisulphite sequencing to chart the epigenome landscape of CAFs at single base resolution. Our data revealed that NPFs and CAFs from localized prostate cancer have remarkably different epigenome profiles characterized by locus-specific rather than global changes in DNA methylation. CAFs exhibited more than 7500 differentially methylated regions compared to NPFs. In contrast, no recurrent genomic aberrations were detected in CAFs, emphasising the importance of epigenome changes in reinforcing their pro-tumorigenic phenotype. Many differentially methylated regions occurred at known regulatory loci and were associated with differentially expressed genes measured using RNAseq. The methylation and gene expression changes were highly consistent across patients when validated using an independent cohort of patient-matched NPFs and CAFs. Remarkably, a subset of differentially methylated regions in CAFs is shared with prostate cancer epithelial cells, revealing the new concept of tumour-specific epigenome modifications in the tumour and its microenvironment. Collectively, these data demonstrate that CAFs are defined by an enduring epigenetic signature that comprises a distinct set of locus-specific DNA methylation alterations in cancer-related regulatory loci. The distinct methylome of CAFs provides a novel epigenetic hallmark of the cancer microenvironment and promises new biomarkers to improve interpretation of diagnostic samples. Citation Format: Mitchell G. Lawrence, Ruth Pidsley, Elena Zotenko, Birunthi Niranjan, Aaron Statham, Jenny Song, Nicola Armstrong, John Pedersen, Mark Frydenberg, Renea Taylor, Clare Stirzaker, Gail Risbridger, Susan Clark. Charting the DNA methylation landscape of prostate cancer associated 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 1997. doi:10.1158/1538-7445.AM2017-1997
Abstract 861: Olfactomedin 4 downregulation is associated with enhancing epithelial-mesenchymal transition in human benign prostate cells and prostate cancer cells
Authors: Hongzhen Li, Wenli Liu, Jianqiong Zhu, Kay Chin, Jaime Rodriguez-Canales, Griffin P. Rodgers
Journal: Cancer Research (2017)

Abstract We have previously reported that lost or reduced olfactomedin 4 (OLFM4) expression is caused by deletions within the OLFM4 gene in 10-25% of all human prostate-cancer samples, and that its expression is lost in more than 58% of advanced prostate-cancer samples. Therefore, we sought to study the role of epigenetic factors in the regulation of OLFM4 gene expression in normal prostate, as well as prostate-cancer, cell lines. Pyrosequencing of genomic DNA extracted from normal prostate or prostate-cancer tissue cells demonstrated that three of the eight CpG sites in the OLFM4 gene promoter were significantly hypermethylated in prostate cancer compared with normal tissue. Exposure to the methylation inhibitor 5-azadeoxycytidine (5-Aza 5 μM) significantly increased OLFM4 expression in RWPE1 benign prostate cells. Knockdown of OLFM4 expression in RWPE benign prostate cells reduced autophagy and enhanced the epithelial-mesenchymal transition (EMT). Restoration of OLFM4 expression in metastatic prostate-cancer cells lacking OLFM4 inhibited cell growth in both in vitro culture models and an in vivo xenograft tumor model, and also inhibited EMT marker gene expression in these cells. 5-Aza induced OLFM4 expression in PC-3 prostate cancer cells and OLFM4 shRNA transfected PC-3 cells affects 5-Aza mediated cell proliferation compared to control-shRNA transfected PC-3 cells. Taken together, our results suggest that OLFM4 inhibits the EMT program in both normal prostate and prostate-cancer cells, and may play a critical role in regulating the EMT program during the progression of cancer. They also suggest that modulation of OLFM4 expression might be a novel molecular target for advancing prostate-cancer therapies. Citation Format: Hongzhen Li, Wenli Liu, Jianqiong Zhu, Kay Chin, Jaime Rodriguez-Canales, Griffin P. Rodgers. Olfactomedin 4 downregulation is associated with enhancing epithelial-mesenchymal transition in human benign prostate cells and prostate 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 861. doi:10.1158/1538-7445.AM2017-861
Abstract #5576: Celecoxib results in hypoxia-independent transcriptional activation of VEGF in a process requiring p38-MAP kinase and Sp1
Authors: Kaiming Xu, Hui-Kuo Shu
Journal: Cancer Research (2009)

Increasing evidence indicates that cyclooxygenase-2 (COX-2) plays a critical role in the initiation and maintenance of many cancer types. Given that increased COX-2 expression have been linked to increased angiogenesis and, with malignant gliomas and other tumor types, a worse prognosis, we became interested in assessing the response of glioma cell lines to treatment with celecoxib, a selective COX-2 inhibitor. Interestingly, contrary to its reported anti-angiogenic effects, we found that treatment with celecoxib (15-30 \#956;M) actually induced the expression of vascular endothelial growth factor (VEGF) mRNA and protein in multiple glioma cell lines. The degree of induction was comparable to, if not greater than, that found after exposure of these cells to hypoxia. This phenomenon was not restricted to glioma cell lines with multiple breast, colon, head and neck, and prostate carcinoma lines also showing similar responses at the mRNA level. Through experiments utilizing pharmacological inhibition and siRNA silencing of expression, p38-MAPK and the Sp1 transcription factor were both found to be required for celecoxib-induced VEGF expression. Consistent with the documented role of the Sp1 transcription factor in this effect, increased VEGF expression was found to be due to transcriptional activation and not changes in the stability of VEGF mRNA. We speculate that treatment with celecoxib may, in some instances, enhance tumor cell expression of VEGF and, consequently, may have detrimental effects on the response of tumors to this drug. This response gives further rationale for potentially combining celecoxib with an anti-VEGF therapy.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5576.
Abstract 2354: Identification of CDK1 as an aspirin and salicylic acid binding protein: a potential role in chemoprevention
Authors: Jayarama B. Gunaje, D.Ramesh Kumar, Siddharth Kesharwani, Eduardo Callegari, Hemachand Tummala, Rakesh Dachineni
Journal: Cancer Research (2017)

Abstract Data emerging from the past 10 years have consolidated the rationale for investigating the use of aspirin for chemoprevention; however, the mechanisms leading to its anti-cancer effects are still being elucidated. We hypothesized that aspirin’s ability to exert chemopreventive effects may involve altering the levels and activity of cell cycle regulatory proteins. In the present study, using HT-29 colon cancer cells and other cancer cells, we demonstrated that both aspirin and its primary metabolite, salicylic acid, downregulated the protein and mRNA levels of cyclin B1 and cyclin dependent kinase-1 (CDK1). Lactacystin, a 26S proteosomal inhibitor, prevented aspirin and salicylic acid mediated degradation of cyclin B1, but not CDK1. Decrease in protein levels of cyclin B1/CDK1 was correlated with a corresponding decrease in CDK1 kinase activity. Molecular docking studies showed that aspirin and salicylic acid independently can dock on CDK1 through interactions with Leucine 83. Incubation of recombinant CDK1 with aspirin resulted in acetylation at lysine residues, this was also observed in cell culture experiments. Pre-incubation of CDK1 with salicylic acid dose dependently prevented aspirin’s ability to acetylate CDK1 in purified preparations confirming the data obtained from molecular docking studies. Our results show that CDK1 is a salicylic acid binding protein (SABP) and the chemopreventive actions of aspirin may involve modulation of levels and activity of cyclin B1 and CDK1. Citation Format: Jayarama B. Gunaje, D.Ramesh Kumar, Siddharth Kesharwani, Eduardo Callegari, Hemachand Tummala, Rakesh Dachineni. Identification of CDK1 as an aspirin and salicylic acid binding protein: a potential role in chemoprevention [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 2354. doi:10.1158/1538-7445.AM2017-2354
Dexmedetomidine in Patients With Sepsis Requiring Mechanical Ventilation
Authors: Christian S. Scheer, Sven-Olaf Kuhn, Sebastian Rehberg
Journal: JAMA (2017)

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Abstract 301: Prognostic value of metastatic tumoral caveolin-1 expression in patients with resected gastric cancer
Authors: Jihyung Hong, Der Sheng Sun, Soon Auck Hong, Hye Sung Won, Han Hong Lee, Okran Kim, Yoon Ho Ko
Journal: Cancer Research (2017)

Abstract Background : Caveolin-1 (Cav-1), as the main component of caveolae, has complex roles in tumourigenesis and clinical outcomes in a variety of human malignancies. We investigated Cav-1 in primary and metastatic tumor of gastric cancer (GC) and its association with clinical outcomes. Method : All specimens evaluated were obtained from 145 patients with GC who had undergone curative gastrectomy. The primary outcomes measured were the expression levels of Cav-1 by immunohistochemistry and its association with clinicopathologicalparameters and patient survival. Results : Among the 145 patients, the frequency of high expression of stromal Cav-1 within primary tumor and tumoral Cav-1 protein in metastatic lymph node were 22.5% (18/145) and 16.6% (15/91). In the multivariate analysis tumoral Cav-1 protein in metastatic lymph node showed prognostic significance for relapse-free survival (RFS, HR, 3.934; 95% CI, 1.882-8.224; P&amp;lt;0.001) and cancer-specific survival outcome (CSS, HR, 3.985; 95% CI, 1.620 - 8.623; P = 0.002). In addition, it remained as a strong indicator of poor prognosis for RFS (HR, 3.137; 95% CI, 1.445 - 6.810; P = 0.004) and CSS (HR, 2.509; 95% CI, 1.079 - 5.838; P = 0.033). Conclusions : High expression of tumoral Cav-1 protein in metastatic lymph node shows a strong negative association with the clinical outcomes in patients with curatively resected GC, suggesting that this protein have potential uses as novel prognostic markers. Citation Format: Jihyung Hong, Der Sheng Sun, Soon Auck Hong, Hye Sung Won, Han Hong Lee, Okran Kim, Yoon Ho Ko. Prognostic value of metastatic tumoral caveolin-1 expression in patients with resected gastric 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 301. doi:10.1158/1538-7445.AM2017-301
Abstract 1987: Inhibition of collagen receptor discoidin domain receptor-1 (DDR1) reduces gastric cancer cell motility and metastasis
Authors: Ryo Yuge, Yasuhiko Kitadai, Hidehiko Takigawa, Shinji Tanaka, Kazuaki Chayama, Wataru Yasui
Journal: Cancer Research (2017)

Abstract Accumulating evidences suggest that a unique set of receptor tyrosine kinases, known as discoidin domain receptors (DDRs), play a role in cancer progression by interaction with their surrounding collagen matrix. Although abnormal expression of DDRs is reported in some human cancers, little is known about the expression and function of DDRs in gastric cancer progression. In this study, we investigated expression and the role of DDR1 in the tumor progression of human gastric cancer. The expression and distribution of DDR1 was analyzed by immunohistochemistry in 127 human gastric cancer cases, and the expression level of DDR1 in 7 human gastric cancer cell lines was analyzed by RT-PCR and western blotting. Proliferation, migration, invasion, and tube formation assays were conducted in DDR1 silenced gastric cancer cells. The effect of DDR1 on the tumor growth and metastasis were examined in orthotopically implanted nude mice model and a model of liver metastasis. DDR1 was expressed in human gastric cancer cell lines, and expression of DDR1 in human gastric tumor was associated with poor prognosis. Among 7 gastric cancer cell lines, MKN74 expressed DDR1 at highest level. DDR1-silenced MKN74 cells showed unaltered proliferation activity. In contrast, migration, invasion, and tube formation were significantly reduced. When examined in an orthotopic nude mouse model, DDR1-silenced implanted tumor significantly decreased angiogenesis and lymphangiogensesis, thereby leading to reduction of lymph node metastasis and liver metastasis. We showed that treatment of DDR1 inhibitor also inhibited lymph node metastasis in an orthotopic nude mouse model These results suggest that DDR1 is involved in GC tumor progression and metastasis. DDR1 could be not only an independent prognostic classifier, but also a promising therapeutic target in patients with GC. Citation Format: Ryo Yuge, Yasuhiko Kitadai, Hidehiko Takigawa, Shinji Tanaka, Kazuaki Chayama, Wataru Yasui. Inhibition of collagen receptor discoidin domain receptor-1 (DDR1) reduces gastric cancer cell motility and metastasis [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 1987. doi:10.1158/1538-7445.AM2017-1987
Abstract 1034: Role of KEAP1/NRF2 and TP53 mutations in lung squamous cell carcinoma development and radiation resistance
Authors: Youngtae Jeong, Ngoc Hoang, Henning Stehr, Alexander Lovejoy, Andrew Gentles, Aadel Chaudhuri, Billy Loo, Ash Alizadeh, Maximilian Diehn
Journal: Cancer Research (2017)

Abstract Although lung squamous cell carcinomas (LSCC) comprise a large fraction of non-small cell lung cancers (NSCLCs), their pathogenesis and cell of origin remain incompletely understood and biomarkers that predict therapeutic responses are lacking. Here we describe novel, clinically relevant murine LSCC models driven by inactivation of Trp53 with or without Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal both in vitro and in in vivo, suggesting that Trp53 or Keap1 mutations lead to expansion of mutant stem cell clones. Deletion of Trp53 with or without Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histologic and molecular features of human LSCCs. However, deletion of Trp53 with or without Keap1 in type II pneumocytes (ATIIs) or bronchioalveolar stem cells (BASCs) produced tumors with the features of adenocarcinoma, indicating that ABSCs represent the likely cell of origin for LSCC in this model. Deletion of Keap1 promoted tumor growth, metastasis and resistance to oxidative stress. N-acetylcysteine (NAC) treatment enhanced tumorsphere formation and metastasis in Keap1WT LSCCs, but not in Keap1-/- LSCCs, suggesting that NRF2-ROS pathway activation is the main mediator of Keap1 loss. Finally, Keap1 deletion induced radioresistance in vitro and in vivo in both LSCCs and lung adenocarcinomas (LUADs). Congruous with these findings, KEAP1/NRF2 mutation status strongly predicted risk of local recurrence in NSCLC patients treated with RT and these mutations could be non-invasively identified in circulating tumor DNA. These data suggest that Trp53 and Keap1 mutations in ABSCs play important roles in LSCC initiation and progression and identify KEAP1/NRF2 mutations as predictive biomarkers that could be used for personalization of therapeutic strategies for NSCLCs, and likely other cancers in which they are recurrently mutated. Citation Format: Youngtae Jeong, Ngoc Hoang, Henning Stehr, Alexander Lovejoy, Andrew Gentles, Aadel Chaudhuri, Billy Loo, Ash Alizadeh, Maximilian Diehn. Role of KEAP1/NRF2 and TP53 mutations in lung squamous cell carcinoma development and radiation resistance [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 1034. doi:10.1158/1538-7445.AM2017-1034
Abstract 1153: Heparan sulfate proteoglycans as novel target in cancer precise therapy
Authors: Chiara Falciani, Jlenia Brunetti, Lorenzo Depau, Alessandro Pini, Giulia Riolo, Elisabetta Mandarini, Luisa Bracci
Journal: Cancer Research (2017)

Abstract Heparan sulfate proteoglycans (HSPGs) have crucial regulatory roles in tumor onset and progression. HSPGs are composed of a core protein and glycan chains characterized by repeated disaccharide units which can be sulfated at different amount and position. HSPG have enormous structural diversity due to the different possible modifications of the single saccharide units within the polysaccharide, such as position, sulphation and acetylation. As a result HSPG can bind and modulate their binding to signaling molecules such as growth factors, morphogens and chemokines1 . HSPG proved to be important in mediating cancer development and progression by enhancing the binding of growth factors, morphogens and cytokines to their cognate receptors, thus activating signaling pathways that give rise to angiogensis, cell growth and proliferation, together with invasion and metastasis 2-3. NT4 is a branched peptides that targets HSPGs. NT4 specifically binds to sulfated glycosaminoglycans on cancer cells and tissues. NT4 can be conjugated to many different cytotoxic units and tracers. NT4 conjugated to paclitaxel produced tumor regression in a breast cancer orthotopic mouse model 4. NT4 conjugated to tracers can discriminate between tumor and healthy tissue in different human cancer specimen5. We will show the ability of NT4 to drive tracers onto tumor lesions by means of Qdots and in vivo imaging, proving their promising features as theranostics. We will also show NT4 ability to interfere with HSPG- modulated activities such as: tumor cell proliferation, migration and invasion of matrix; as well as endothelial cells proliferation, migration and tube formation. NT4-HSPG interactions and consequent modulation of signaling pathways will prove the importance of this versatile tool, NT4, in addressing tumor cells and interfering in their cell-cell and cell-matrix communications. Bibliography 1. Gharbaran R. et al. Tumour Biol. 2016; 37:11573-11588. 2. Purushothaman A et al. Blood. 2010; 115:2449-57. 3. Lee JH et al. J Biol Chem. 2009; 284:27167-75. 4. Brunetti, J. et al. Scientific Reports. DOI:10.1038/srep17736 5. Falciani C. et al. J Med Chem. 2013; 56:5009-18. Citation Format: Chiara Falciani, Jlenia Brunetti, Lorenzo Depau, Alessandro Pini, Giulia Riolo, Elisabetta Mandarini, Luisa Bracci. Heparan sulfate proteoglycans as novel target in cancer precise therapy [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 1153. doi:10.1158/1538-7445.AM2017-1153
Abstract 160: Contribution of IP3 Receptors in the Electromechanical Response of LV Myocytes to Gq-protein Coupled Receptor Agonists
Authors: Sergio Signore, Andrea Sorrentino, Antonio Cannata, Chiara Mangiaracina, Mark Sundman, João Ferreira-Martins, Ramaswamy Kannappan, Mehrdad Shafaie, Andrew Webster, Fumihiro Sanada, Ewa Wybieralska, Barbara Ogórek, Giulia Borghetti, Polina Goichberg, Marcello Rota
Journal: Circulation Research (2013)

Gq-protein coupled receptor (GPCR) stimulation promotes PLC function, generating diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). The latter may promote Ca2+ translocation from intracellular stores altering Ca2+ homeostasis in cardiomyocytes. The aim of this study was to establish whether GPCR agonists enhance IP3 receptor (IP3R) activity, affecting the electromechanical properties of LV myocytes. For this purpose, the functional responses of myocytes to GPCR agonists ATP or ET-1 were established. In field-stimulated cells, GPCR activators increased diastolic Ca2+, transient amplitude, and contractility; extra-systolic Ca2+ releases and aftercontractions were promoted. These responses were prevented by inhibition of PLC, or blockade of IP3Rs. Since DAG promotes PKC activity, the effects of GPCR stimulation were tested in the presence of the PKC inhibitor chelerythrine. This compound failed to abrogate the effects of ATP and ET-1, indicating that PKC-independent pathways play a critical role in mediating the observed cellular responses to GPCR stimulation. Additionally, an AAV9 vector carrying EGFP and sh-RNA targeting IP3R type-2 was employed in vivo to downregulate IP3Rs. GPCRs activation failed to increase Ca2+ transients and to induce extra-systolic Ca2+ elevations in EGFP-positive myocytes. Conversely, these responses were preserved in EGFP-negative cells. In patch-clamped myocytes, changes in Ca2+ transient properties following GPCR activation were accompanied by a decrease in resting potential, action potential (AP) prolongation, and emergence of arrhythmic events. Similar electrical disturbances were detected by direct activation of IP3R with IP3 dialysis, or by enhancing the affinity of the receptors to its ligand, with thimerosal. To establish whether Ca2+ mobilized from the sarcoplasmic reticulum (SR) to the cytoplasm via IP3Rs was responsible for the electrical alterations caused by GPCR agonists, experiments were performed in which SR Ca2+ was depleted, or cytosolic Ca2+ was buffered. Under these conditions, ATP and ET-1 failed to prolong the AP and to induce arrhythmias. In conclusion, the GPCR/IP3R axis regulates Ca2+ homeostasis, contractile performance and the electrical stability of LV myocytes.