tbuckley/cabot-search huggingface dataset:
Abstract LB-067: Identifying novel and druggable targets in a triple negative breast cancer cell line using the Invitrogen LentiArray Human Kinase CRISPR Library
Authors: Tufan Gokirmak, Jason Sharp, Chetana Revankar, David R. Piper
Journal: Cancer Research (2018)

Abstract Breast cancer is the most commonly diagnosed cancer among women in worldwide and the second leading cause of death by cancer after lung cancer. Breast cancer can be broadly grouped into three main groups: HR+ (estrogen receptor positive and/or progesterone receptor positive), HER2+ (human epidermal growth factor receptor 2 positive) and triple-negative (HR- and HER2-). Hormone and anti-HER2 targeted therapies are available for receptor positive breast cancer types. However, because triple-negative breast cancer (TNBC) does not have estrogen, progesterone or HER2 receptors, there are no such targeted therapies available for this type of cancer. Currently, oncologists are resort to treating TNBC patients with traditional chemotherapy drugs, surgery and radiation. Thus, due to its poorer prognosis and fewer treatment options in comparison to other type of breast cancers, search for specific molecular targets and developing novel treatments for TNBC is one of the highest priorities of current breast cancer research. Protein kinases are involved in cell signaling cascades leading to cell proliferation, migration and survival in all cell types, and their dysregulation often leads to cancer. Due to their oncogenic roles, protein kinases have become a main focus of the targeted drug discovery efforts. Therefore development of novel high-throughput screening platforms that enable the identification of protein kinases or for that matter any gene, essential for tumor proliferation and viability is expected to advance oncogenic drug discovery efforts. In this study, we developed a loss-of-function screen for identifying essential kinases in a TNBC cell line, MDA-MB-231, using the Invitrogen™ LentiArray™ Human Kinase CRISPR Library. This arrayed lenti virus library targets 840 kinases with up to 4 different gRNAs per protein kinase for complete gene knockout. Our initial pilot screen identified polo-like kinase 1 (PLK1), checkpoint kinase 1 (CHK1) and cyclin-depended kinase 9 (CDK9) as essential kinases in MDA-MB-231 cell line and our current efforts focus on expanding this loss-of-function screen to the full kinase library and validation of the hits. Target identification and validation remains a significant challenge to translate to clinical trial outcomes and these generalized, functional genomic approaches may provide the next-generation platform to effectively bridge these gaps. Citation Format: Tufan Gokirmak, Jason Sharp, Chetana Revankar, David R. Piper. Identifying novel and druggable targets in a triple negative breast cancer cell line using the Invitrogen LentiArray Human Kinase CRISPR Library [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 LB-067.
Abstract 20541: MicroRNA-216a Mediates the Activation of Telomerase in Macrophages Differentiation via the Smad3/NF-κB Pathway
Authors: Shujun Yang, Jian Li, Yu Chen, Rutai Hui, Weili Zhang
Journal: Circulation (2016)

Background: The monocyte/macrophage is a central participant in the inflammatory process that is involved in all stages of atherosclerosis. Our previous work showed that telomerase reverse transcri...
Abstract 3952: Selective high affinity MYC-binding compound inhibits MYC-MAX interaction and MYC-dependent tumor cell growth
Authors: Alina Castell, Qinzi Yan, Karin Fawkner, Per Hydbring, Fan Zhang, Vasiliki Verschut, Marcela Franco, Giovanna Zinzalla, Lars-Gunnar Larsson
Journal: Cancer Research (2018)

Abstract The MYC family oncoproteins/transcription factors MYC, MYCN and MYCL (here referred to as MYC) are key players in tumor development and are particularly associated with aggressive disease and poor prognosis. Efficient and specific MYC-targeting drugs are therefore highly warranted, but no such drugs are available in the clinic at present. MYC is strictly dependent on heterodimerization with MAX for activation of transcription. In a cell-based Bimolecular Fluorescence Complementation protein-protein interaction screen for small molecule inhibitors we identified a molecule that exhibits strong selective inhibition of MYC-MAX interaction in cells as validated by Gaussia luciferase protein complementation assay, coimmunoprecipitation and in situ proximity ligation (isPLA) assay, reaching an IC50 at single-digit micromolar concentrations. The molecule was shown to inhibit MYC-MAX interactions in a biochemical FRET assay and binds selectively to the MYC bHLHZip domain with affinity in the single digit micromolar range as demonstrated by Microscale Thermophoresis and Surface Plasmon Resonance. Further, within the same concentration range, this molecule blocks MYC-driven transcription and efficiently inhibits tumor cell growth in a MYC-dependent manner, but spares normal cells. Moreover, the growth inhibitory responses to the molecule correlated significantly with MYC expression levels in a cohort of 60 human tumor cell lines. Importantly, utilizing a mouse tumor model of MYCN-amplified neuroblastoma, treatment with the molecule resulted in significant inhibition of the MYC-MAX interaction in tumor tissue, as shown by isPLA, and massive induction of apoptosis in the tumors. Since this molecule, unlike many experimental MYC inhibitors, is selective, has high affinity for MYC, has high efficacy in cells, reaches its target in vivo and does not affect MYC expression levels, it can be used as a chemical tool to specifically study the role of the MYC-MAX complex in MYC biology in normal and cancerous cells, and it has potential for drug development. Citation Format: Alina Castell, Qinzi Yan, Karin Fawkner, Per Hydbring, Fan Zhang, Vasiliki Verschut, Marcela Franco, Giovanna Zinzalla, Lars-Gunnar Larsson. Selective high affinity MYC-binding compound inhibits MYC-MAX interaction and MYC-dependent tumor cell growth [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 3952.
P2Y12 antagonists and cardiac repair post-myocardial infarction: global and regional heart function analysis and molecular assessments in pigs
Authors: Gemma Vilahur, Manuel Gutiérrez, Laura Casani, Carmen Lambert, Guiomar Mendieta, Soumaya Ben-Aicha, Antoni Capdevila, Guillem Pons-Lladó, Francesc Carreras, Leif Carlsson, Alberto Hidalgo, Lina Badimon
Journal: Cardiovascular Research (2018)

P2Y12 antagonists are the standard in antiplatelet therapy but their potential effects on functional myocardial recovery and cardioprotection post-myocardial infarction (MI) are unknown. We investigated in a preclinical model of MI whether ticagrelor and clopidogrel differently affect cardiac repair post-MI.Pigs either received: (i) clopidogrel (600 mg; 75 mg/qd); (ii) ticagrelor (180 mg; 90 mg/bid); and (iii) placebo control. MI was induced by mid-left anterior descending coronary artery balloon occlusion (60 min) and animals received the maintenance doses for the following 42 days. Serial cardiac magnetic resonance was performed at Day 3 and Day 42 for the assessment of global and regional cardiac parameters. We determined cardiac AMP-activated protein kinase (AMPK), Akt/PKB, aquaporin-4, vascular density, and fibrosis. In comparison to controls, both P2Y12 antagonists limited infarct expansion at Day 3, although ticagrelor induced a further 5% reduction (P < 0.05 vs. clopidogrel) whereas oedema was only reduced by ticagrelor (≈23% P < 0.05). Scar size decreased at Day 42 in ticagrelor-treated pigs vs. controls but not in clopidogrel-treated pigs. Left ventricular ejection fraction was higher 3 days post-MI in ticagrelor-treated pigs and persisted up to Day 42 (P < 0.05 vs. post-MI). Regional analysis revealed that control and clopidogrel-treated pigs had severe and extensive wall motion abnormalities in the jeopardized myocardium and a reduced myocardial viability that was not as evident in ticagrelor-treated pigs (χ2P < 0.05 vs. ticagrelor). Only ticagrelor enhanced myocardial AMPK and Akt/PKB activation and reduced aquaporin-4 levels (P < 0.05 vs. control and clopidogrel). No differences were observed in vessel density and fibrosis markers among groups.Ticagrelor is more efficient than clopidogrel in attenuating myocardial structural and functional alterations post-MI and in improving cardiac healing. These benefits are associated with persistent AMPK and Akt/PKB activation.
Determinants and Consequences of Financial Hardship Among Adult Survivors of Childhood Cancer: A Report From the St. Jude Lifetime Cohort Study
Authors: I-Chan Huang, Nickhill Bhakta, Tara M Brinkman, James L Klosky, Kevin R Krull, DeoKumar Srivastava, Melissa M Hudson, Leslie L Robison
Journal: JNCI Journal of the National Cancer Institute (2018)

Abstract Background Financial hardship among survivors of pediatric cancer has been understudied. We investigated determinants and consequences of financial hardship among adult survivors of childhood cancer. Methods Financial hardship, determinants, and consequences were examined in 2811 long-term survivors (mean age at evaluation = 31.8 years, years postdiagnosis = 23.6) through the baseline survey and clinical evaluation. Financial hardship was measured by material, psychological, and coping/behavioral domains. Outcomes included health and life insurance affordability, retirement planning, symptoms, and health-related quality of life (HRQOL). Odds ratios (ORs) estimated associations of determinants with financial hardship. Odds ratios and regression coefficients estimated associations of hardship with symptom prevalence and HRQOL, respectively. All statistical tests were two-sided. Results Among participants, 22.4% (95% confidence interval [CI] = 20.8% to 24.0%), 51.1% (95% CI = 49.2% to 52.9%), and 33.0% (95% CI = 31.1% to 34.6%) reported material, psychological, and coping/behavioral hardship, respectively. Risk factors across hardship domains included annual household income of $39 999 or less vs $80 000 or more (material OR = 3.04, 95% CI = 2.08 to 4.46, psychological OR = 3.64, 95% CI = 2.76 to 4.80, and coping/behavioral OR = 4.95, 95% CI = 3.57 to 6.86) and below high school attainment vs college graduate or above (material OR = 2.22, 95% CI = 1.45 to 3.42, psychological OR = 1.75, 95% CI = 1.18 to 2.62, and coping/behavioral OR = 2.05, 95% CI = 1.38 to 3.06). Myocardial infarction, peripheral neuropathy, subsequent neoplasm, seizure, stroke, reproductive disorders, amputation, and upper gastrointestinal disease were associated with higher material hardship (all P &lt; .05). Hardship across three domains was associated with somatization, anxiety and depression (all P &lt; .001), suicidal ideation (all P &lt; .05), and difficulty in retirement planning (all P &lt; .001). Survivors with hardship had statistically significantly lower HRQOL (all P &lt; .001), sensation abnormality (all P &lt; .001), and pulmonary (all P &lt; .05) and cardiac (all P &lt; .05) symptoms. Conclusions A substantial proportion of adult survivors of childhood cancer experienced financial hardship. Vulnerable sociodemographic status and late effects were associated with hardship. Survivors with financial hardship had an increased risk of symptom prevalence and impaired HRQOL.
Abstract 79: Stromal regulation of prostate cancer cell proliferation by mevalonate pathway enzymes HMGCS1 and HMGCR
Authors: Shingo Ashida, Chiaki Kawada, Keiji Inoue
Journal: Cancer Research (2018)

Abstract It has been suggested that the tumor microenvironment plays an important role in tumor progression, acquisition of androgen independence, and distant metastasis in prostate cancer (PC). However, little is known about the transcriptional basis of cellular interactions in the human PC microenvironment. To clarify the mechanism of PC progression and metastasis, we investigated the interaction of PC, epithelial, and stromal cells by analyzing genome-wide gene expression profiles. Our hypothesis is that PC cells could induce stromal cells to differentiate into so-called cancer-associated fibroblasts (CAFs), which might contribute to cancer invasion and metastasis. We identified the up-regulated genes in normal human prostate stromal cells (PrSC) co-cultured with human PC cells (LNCaP), which included the mevalonate pathway enzymes 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Knockdown of endogenous HMGCS1 or HMGCR in PC cells by shRNA resulted in a significant reduction of PC cell viability. Importantly, exogenous overexpression of HMGCS1 or HMGCR in either PC cells or prostate stromal cells stimulated PC cell growth, suggesting a possible autocrine/paracrine regulation. Immunohistochemical analysis confirmed that HMGCS1 and HMGCR were overexpressed in PC stroma, especially in the early stage of PC. These results provide clues to the molecular mechanisms underlying PC invasion and metastasis, and suggest that HMGCS1 and HMGCR in PC, as well as in PC stroma, might serve as molecular targets for the treatment of PC. Citation Format: Shingo Ashida, Chiaki Kawada, Keiji Inoue. Stromal regulation of prostate cancer cell proliferation by mevalonate pathway enzymes HMGCS1 and HMGCR [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 79.
Correlation of multidrug-resistance gene (MDR1) expression levels and outcome to adjuvant cisplatin/MTX based chemotherapy in patients enrolled in the AUO-AB 05/95 phase III trial
Authors: A. C. Hoffman, P. Wild, T. Gauler, C. Leicht, S. Bertz, K. D. Danenberg, P. V. Danenberg, R. Stöhr, M. Stöckle, J. Lehmann, A. Hartmann
Journal: Journal of Clinical Oncology (2009)

5026 Background: The human MDR1 gene encodes an integral membrane protein, P glycoprotein (Pgp), whose function is the energy dependent export of substances from the inside of cells, and from membranes, to the outside. MDR1 mRNA levels have been shown to influence metabolism of cancer drugs. We tested whether MDR1 gene expression is associated with outcome in patients with locally advanced bladder cancer. Methods: 221 formalin fixed paraffin embedded (FFPE) tumor samples from patients with locally advanced and/or lymph node-positive bladder cancer enrolled for adjuvant therapy in the AUO-AB 05/95 phase III trial (Lehmann et al, J Clin Oncol. 2005;23:4963–4974) were analyzed (110 pts treated with cisplatin/MTX, 101 pts treated with MTX, vinblastine, epirubicin, and cisplatin, M-VEC).FFPE tissues were dissected using laser-captured microdissection and analyzed for MDR1 and ERCC1 mRNA expression using a quantitative real-time RT-PCR method. Gene expression values (relative mRNA levels) are expressed as ratios between the target gene and internal reference gene (beta-actin). Results: MDR1 was significantly correlated to progression free and overall survival. We included tumor stage (pT), lymph node status (pN) and the blood vessel invasion along with the measured gene expression in a stepwise multivariate Cox proportional hazards regression model. The overall model fit had a significance level of p = 0.0001 (&lt;0.05). The relative risk for shorter survival in patients with High MDR1 expression was 2.8. Regarding survival MDR1 was strongly associated to ERCC1 expression in patients with M-VEC treatment. Conclusions: These results suggest that MDR1 gene expression levels predict response and overall survival in patients with locally advanced urothelial cancer enrolled in AUO-AB 05/95. MDR1 gene expression levels may allow the selection of patients who benefit likely from adjuvant cisplatin/MTX based chemotherapy. Further studies are warranted to study this association. [Table: see text]
Abstract 3353: ZNF414 as a functionally relevant transcription factor in pancreatic and breast cancer cells
Authors: Alejandra Rodríguez Martínez, Elisa M. Vuorinen, Anastasia Shcherban, Nina K. Rajala, Matti Nykter, Anne Kallioniemi
Journal: Cancer Research (2018)

Abstract Background: The Zinc Finger Protein 414 (ZNF414) is a member of the krüppel C2H2-type zinc-finger protein family. ZNF414 is a cargo protein for Karyopherin α7 (KPNA7), a nuclear importer expressed during embryogenesis, absent in most adult tissues but re-expressed in cancer cells. KPNA7 is involved in promoting proliferation and maintaining nuclear morphology in several breast and pancreatic cancer cell lines. Similar effects on cell growth have been evidenced for ZNF414 using in vitro knock-down experiments. Other than this, the function of ZNF414 remains uncharacterized but, as a zinc finger protein with nuclear localization, it is likely to act as a transcription factor. This study aimed at identifying target genes and DNA binding motifs of ZNF414 in pancreatic and breast cancer cells. Methods: We used next generation sequencing methods on Hs700T and MCF-7 cell lines. RNA-seq was used to identify genes regulated by ZNF414 and ChIP-exo and ATAC-seq analyses to uncover its genomic binding regions. Samples for RNA-seq were collected 12h and 24h after transfection with siRNAs targeting ZNF414. For ChIP-exo and ATAC-seq experiments, cells were transfected to transiently overexpress V5-tagged ZNF414. Results: RNA-seq data analyses revealed 33 and 296 differentially expressed genes (DEGs) in Hs700T cells at 12h and 24h time points, respectively. The corresponding amounts of DEGs in MCF-7 cell line were 177 and 556. There were 23 and 108 DEGs in common to both cell lines at 12h and 24h, respectively. Interestingly, gene ontology analyses revealed enrichment of many functional categories related to cellular proliferation in both cell lines, providing a molecular explanation for the observed ZNF414-elicited phenotype. ChIP-exo data was processed using MACE tool and then combined with the ATAC-seq open chromatin signal to identify the most reliable peaks. We looked at the genomic location of these peaks and observed clear enrichment in the promoter and 5'UTR regions, indicating that ZNF414 is a classical transcription factor. Using MEME for de novo motif discovery analyses, we identified several putative binding motifs common to both cell lines, some of which were also found in promoters of DEGs. Conclusion: This study uncovered the transcriptional regulation that underlies the role of ZNF414 as inducer of cellular proliferation in pancreatic and breast cancer cells. Citation Format: Alejandra Rodríguez Martínez, Elisa M. Vuorinen, Anastasia Shcherban, Nina K. Rajala, Matti Nykter, Anne Kallioniemi. ZNF414 as a functionally relevant transcription factor in pancreatic and breast cancer cells [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 3353.
Abstract 5670: Systemic lymphoid architecture response assessment (SYLARAS): Application to system-wide immunophenotyping of glioblastoma
Authors: Gregory J. Baker, Sucheendra K. Palaniappan, Jodene K. Moore, Stephanie H. Davis, Peter K. Sorger
Journal: Cancer Research (2018)

Abstract Interactive flow cytometry analysis software allows users to make binary decisions on immunomarker status of single cells through arbitrary placement of one- and two- dimensional gates. However, manual gating through a point-and-click graphical user interface (GUI) is impractical for large datasets. Here we describe SYLARAS, a suite of experimental and computational tools for the systematic and chronological evaluation of lymphoid tissue architecture. SYLARAS takes multiplex single-cell data as input, bins cells in n-dimensional orthant space, and returns schematized summary statistics on immunophenotypes of interest. We programmatically curated data on 33 immunophenotypes constituting primary and secondary lymphoid tissue of immunocompetent mice bearing syngeneic, orthotopic glioblastoma (GBM) at 3 stages of tumor growth. SYLARAS permitted the discovery of tumor-induced immune signatures whose divergence from mock engrafted, age-matched controls was quantified and statistically analyzed. By integrating information on peripheral immune composition with the levels of 111 blood cytokines of the same mice, we uncovered novel cell types, cytokines, and correlation networks perturbed by the mouse GL261 glioma model. SYLARAS facilitates the discovery of immune regulatory mechanisms and their response to therapy and is broadly applicable to the fields of immuno-oncology, autoimmunity, and infectious disease. Citation Format: Gregory J. Baker, Sucheendra K. Palaniappan, Jodene K. Moore, Stephanie H. Davis, Peter K. Sorger. Systemic lymphoid architecture response assessment (SYLARAS): Application to system-wide immunophenotyping 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 5670.
Abstract 10036: Olmesartan Improves Not Only Vascular Endothelial Dysfunction but Cardiac Diastolic Dysfunction in Hypertensive Heart Failure With Preserved Ejection Fraction - ORION Study
Authors: EiichiroYamamoto, KeisukeOhba, YoshihiroHirata, TakanoriTokitsu, KoichiSugamura, SeijiHokimoto, SeigoSugiyama, HisaoOgawa
Journal: Circulation (2015)

Introduction: The optimal treatment for heart failure (HF) with preserved left ventricular (LV) ejection fraction (EF) (HFpEF) has not been established. Using an experimental model of HFpEF, we previously reported a novel mechanism underlying reversal of endothelial dysfunction and HFpEF by AT1 receptor blocker (ARB). By performing this study (ORION: OlmesaRtan Improvement endothelial functiON with hypertension study), we examined the effects of ARB on hypertensive HFpEF patients, focusing on reactive oxygen species (ROS). Methods and Results: We examined prospectively 20 hypertensive HFpEF patients, taking any renin-angiotensin system inhibitors, switched to appreciable amounts of highly-selective ARB; olmesartan (average dosage amounts: 22.9 mg/day) for 3 months. Despite no additive hypotensive effects of olmesartan, endothelial dysfunction assessed by fingertrip digital reactive hyperemia (RH) peripheral arterial tonometry using Endo-PAT2000 was significantly reversed (RH-index; 1.57±0.34 to 1.87±0.50,...
Abstract 14997: Increase in Cerebral Oxygenation During Pre-Hospital Cpr is Associated With Rosc, a Multicenter Study
Authors: Cornelia Genbrugge, Ward Eertmans, Frank Jans, Willem Boer, Cathy De Deyne
Journal: Circulation (2016)

Introduction: During pre-hospital CPR monitoring possibilities are limited. In particular specific and reliable information about the brain is absent during CPR leaving physicians unaware of the ef...