tbuckley/cabot-search huggingface dataset:
Abstract 1186: Intratumoral heterogeneity in small cell carcinoma of the lung: An evolutionary and ecologic process
Authors: Craig D. Peacock, Priyanka Gopal, Aaron Petty, Kevin Rogacki, Mohamed E. Abazeed
Journal: Cancer Research (2018)

Abstract It is increasingly apparent that tumors represent dynamic structures in which cell populations, defined by genetic, epigenetic and non-genetic variation, compete for space and resources, while attempting to evade host defenses, resist therapeutic interventions and colonize new environments. Yet, the extent of this intratumoral genetic heterogeneity and the rules governing this ecosystem remain largely unknown. Using a large inventory of patient-derived xenograft models and an ex vivo culture system that maintains the transcriptional fidelity of the primary tumors, we have interrogated small cell lung cancer (SCLC) as a tractable model system for studying tumor evolution. In the process, we have identified at least three morphologically distinct intratumoral subpopulations across several samples: (i) suspended aggregates of small cells (neuroendocrine or NE), (ii) larger, pleomorphic cells with visible cytoplasm and spindle-like membrane extensions growing as a monolayer (mesenchymal or MS) and (iii) pre-suspension aggregates that are nested above mesenchymal-like cells (proneural or PN). Moreover, we have shown that these subpopulations are functionally distinct as measured by cellular proliferation, migration/invasion ability and sensitivity to chemotherapy/radiation. Intriguingly, distinct inter-tumoral transcriptional states assembled from earlier analyses of SCLC gene expression values across 53 and 71 cell lines and primary tumors, respectively, were preserved in the three intratumoral subpopulations within our examined SCLC lines. The proportion of each well-defined subpopulation varied across samples, suggesting sample-specific fractional setpoints. Finally, we have identified transcription factors that function as central nodes in the gene expression networks of each population and have used computational tools to nominate and functionally confirm biological processes within each population. Namely, we have shown that ASCL1 marks the rapidly proliferating NE population, NEUROD1 marks the primitive PN population and YAP1 marks the slow-growing MS population. We posit that understanding the SCLC ecosystem will provide substantial insight into its biological and clinical behavior and advance therapeutic possibilities in this recalcitrant disease. Citation Format: Craig D. Peacock, Priyanka Gopal, Aaron Petty, Kevin Rogacki, Mohamed E. Abazeed. Intratumoral heterogeneity in small cell carcinoma of the lung: An evolutionary and ecologic process [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 1186.
Predictors of Improvement of Unrepaired Moderate Ischemic Mitral Regurgitation in Patients Undergoing Elective Isolated Coronary Artery Bypass Graft Surgery
Authors: MartinPenicka, HanaLinkova, OttoLang, RichardFojt, ViktorKocka, MarcVanderheyden, JozefBartunek
Journal: Circulation (2009)

Background— The persistence of moderate ischemic mitral regurgitation (IMR) after isolated coronary artery bypass graft surgery is an important independent predictor of long-term mortality. The aim of the present study was to identify predictors of postoperative improvement in moderate IMR in patients with ischemic heart disease undergoing elective isolated coronary artery bypass graft surgery. Methods and Results— The study population consisted of 135 patients with ischemic heart disease (age, 65±9 years; 81% male) and moderate IMR undergoing isolated coronary artery bypass graft surgery. Fourteen patients died before the 12-month follow-up echocardiography and were excluded. At the 12-month follow-up, 57 patients showed no or mild IMR (improvement group), whereas 64 patients failed to improve (failure group). Before coronary artery bypass graft surgery, the improvement group had significantly more viable myocardium and less dyssynchrony between papillary muscles than the failure group (P<0.001). All oth...
Abstract 2481: Loss of FUBP1 impairs terminal neuronal differentiation and predisposes neural progenitors for transformation
Authors: Inah Hwang, Dongqing Cao, Do-Yeon Kim, Tuo Zhang, Jian Hu, Yu Yao, Jihye Paik
Journal: Cancer Research (2018)

Abstract Loss of terminal differentiation capacity through genetic mutations is a selected genetic event in tumorigenesis. 1p19q co-deletion associated recurrent mutations of far upstream element-binding protein 1 (FUBP1) have been reported from genomic analysis of low- grade oligodendroglioma. It is frequently overexpressed in many human cancers and strongly correlated with disease progression. However, left unanswered is how FUBP1 serves uniquely as a tumor suppressor in the central nervous system. Here we show that expression of FUBP1 is dynamically regulated during neurogenesis, marking specific stages of neuronal differentiation. Loss of FUBP1 in neural stem/progenitor cells (NPC) increased the number of cells fail to terminally differentiate. Knockdown of FUBP1 further blocks differentiation and promotes tumorigenesis collaboratively with the expression of neomorphic isocitrate dehydrorgenase 1 mutant IDH1R132H. Mechanistically FUBP1 is necessary for mini exon 8a splicing of neurospecific isoform of histone demethylase LSD1 (nLSD1). It binds to intron 8 of LSD1 together with a neuron-specific splicing complex containing NOVA1 and 2 and works synergistically with SRRM4 for the inclusion of mini exon 8a. The expression level of nLSD1 is decreased upon loss of FUBP1 in neural progenitors, impairing the terminal neuronal differentiation and maturation. Reinforcing nLSD1 expression in FUBP1-downregulated NPC restores terminal differentiation, establishing nLSD1 as an obligatory effector of FUBP1-dependent neuronal differentiation. Together, these findings establish a direct role for FUBP1 in neuronal differentiation and also uncover the mechanism for its tumor suppressor function in the nervous system. Citation Format: Inah Hwang, Dongqing Cao, Do-Yeon Kim, Tuo Zhang, Jian Hu, Yu Yao, Jihye Paik. Loss of FUBP1 impairs terminal neuronal differentiation and predisposes neural progenitors for transformation [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 2481.
Abstract 5038: Ready to use 3D spheroid cultures as a standard tool to screen for compounds targeting cancer
Authors: Angel Garcia Martin, Olatz Leis, Juan Gumuzio, Inés Prieto, Estibaliz Ruiz
Journal: Cancer Research (2018)

Abstract The cancer stem cell (CSC) concept has important implications not only for our understanding of carcinogenesis, but also for the development of cancer therapeutics. There is a growing body of preclinical evidence showing that cancer stem cells contribute to chemotherapy and radiation resistance in breast cancer. The use of drugs that interfere with stem cell self-renewal represents the strategy of choice for novel effective anti-cancer treatments, but also a great challenge because cancer stem cells and their normal counterparts share many pathways. The biology of cancer stem cells has proven complex and difficult to translate into effective therapeutic strategies. The question arises as: how do we test compounds for anti-cancer stem cell activity? The answer is: phenotypic screening. There are indeed several functional assays well validated in the scientific literature that have been used for years associated to the ability of cancer cells to demonstrate stem cell behavior. The most relevant is the 3D tumor spheroid assay. This assay has been used to uncover and culture stem cells from many tissues as well as from tumors. There are multiple reports now that show that spheroid derived cells are enriched in tumor initiating or cancer stem cells, derived from cell lines and from natural fresh tumors as well. Here we describe the use of 3D spheroid models to profile compound activity against cancer stem cells. Furthermore, a case of compounds preventing hypoxia-inducible transcription factor (HIFs) activity is presented. Recently, HIF transcription factor biology has been linked to pathways that regulate stem cell self-renewal and pluripotency, suggesting a new mechanism whereby HIF proteins may drive tumor growth, through the generation of tumour-initiating cells or cancer stem cells. Therefore, targeting the HIF pathway may provide a novel therapeutic avenue to target cancer stem cells. We demonstrate that interfering with HIF pathway activation prevents mammosphere formation, validated through indenpendent confirmation through Sox2 promoter activation, Aldefluor® assay and in vivo proof-of concept experiments targeting tumor initiation. Citation Format: Angel Garcia Martin, Olatz Leis, Juan Gumuzio, Inés Prieto, Estibaliz Ruiz. Ready to use 3D spheroid cultures as a standard tool to screen for compounds targeting 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 5038.
A Walnut Diet Improves Endothelial Function in Hypercholesterolemic Subjects
Authors: EmilioRos, IsabelNúñez, AnaPérez-Heras, MercèSerra, RosaGilabert, ElenaCasals, RamónDeulofeu
Journal: Circulation (2004)

Background— Epidemiological studies suggest that nut intake decreases coronary artery disease (CAD) risk. Nuts have a cholesterol-lowering effect that partly explains this benefit. Endothelial dysfunction is associated with CAD and its risk factors and is reversed by antioxidants and marine n-3 fatty acids. Walnuts are a rich source of both antioxidants and α-linolenic acid, a plant n-3 fatty acid. Methods and Results— To test the hypothesis that walnut intake will reverse endothelial dysfunction, we randomized in a crossover design 21 hypercholesterolemic men and women to a cholesterol-lowering Mediterranean diet and a diet of similar energy and fat content in which walnuts replaced ≈32% of the energy from monounsaturated fat. Participants followed each diet for 4 weeks. After each intervention, we obtained fasting blood and performed ultrasound measurements of brachial artery vasomotor function. Eighteen subjects completing the protocol had suitable ultrasound studies. Compared with the Mediterranean di...
Abstract 3631: Passenger fusion genes are novel predictive biomarker of anti-PD-1 antibody nivolumab for ovarian cancer
Authors: Junzo Hamanishi, Ryusuke Murakami, John B. Brown, Tsukasa Baba, Kaoru Abiko, Eiji Suzuki, Masaki Mandai
Journal: Cancer Research (2018)

Abstract Background: Immune checkpoint PD-1 signal blockade provides significant clinical efficacy and durable response for several cancer patients. However it is crucial to identify a biomarker to predict the response to PD-1 signal blockade. Herein we analyzed the somatic mutanomes and transcriptomes of tumor samples from ovarian cancer patients treated with nivolumab to identify potential biomarkers of antitumor response. Methods: We previously reported a phase II clinical trial for resistant ovarian cancer with nivolumab (UMIN000005714) and showed disease control rate was 45% including 2 complete responders. To estimate the somatic mutation burden (TMB) of tumor samples, the number of non-synonymous single nucleotide variants (nsSNVs), insertions and deletions of genes was analyzed by whole exome sequencing of formalin fixed paraffin embedded tumor tissues. Next, to evaluate whole transcriptome of these samples, we performed an RNAseq analysis and detected several fusion genes in some patients. We evaluated the correlation between clinical anti-tumor response for nivolumab treatment with the numbers of somatic mutations or transcriptomic alignments containing gene fusions. Results: 16 tumor samples (7 responders, 9 non-responders and 1 loss) for whole exome sequencing and 17 samples (7 responders and 10 non-responders) for RNA sequencing were available. Contrary to expectations generated by previously reported papers in melanoma or lung cancers, the levels of TMB including nsSNVs, insertions and deletions of genes were not significantly correlated to antitumor response. However, more than 2 fusion genes were detected (mean=6.3, range 0-15) in 6 of 7 responders, while 8 of 10 non-responders did not have any fusion genes and the remaining non-responders had only 1 fusion gene each (mean=0.2, range, 0-1). Therefore an antitumor response to nivolumab was strongly correlated to the number of fusion genes in ovarian cancer (p=0.0003, sensitivity: 86% [6/7] specificity: 100% [10/10]). Conclusions: This study, to our knowledge, is the first to describe passenger fusion genes of tumors, and might provide a clinically useful and novel predictive biomarker of antitumor response to anti-PD-1/PD-L1 antibody therapy for ovarian cancer. Citation Format: Junzo Hamanishi, Ryusuke Murakami, John B. Brown, Tsukasa Baba, Kaoru Abiko, Eiji Suzuki, Masaki Mandai. Passenger fusion genes are novel predictive biomarker of anti-PD-1 antibody nivolumab for 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 3631.
Abstract LB-267: A small molecule mimic approach to the PEDF/LAMR1 interaction in prostate cancer
Authors: Daniel F. Edwards, Charles S. Umbaugh, Marxa L. Figueiredo
Journal: Cancer Research (2018)

Abstract Pigment epithelium derived factor, or PEDF, is a well-known and potent inhibitor of angiogenesis. Our lab as well as others have examined PEDF as a novel prostate cancer therapy, as PEDF inhibits tumor establishment, promotes tumor cell differentiation, and induces tumor apoptosis. PEDF has been identified as a binding partner for the cancer associated protein Laminin Receptor (LAMR1). LAMR1 has been shown to be overexpressed in several types of cancers including breast, colon, and prostate. It has been reported in the literature that the PEDF/LAMR1 interaction inhibits tumor migration and invasion. Recent work in the lab investigated whether we could mimic the PEDF/LAMR1 interaction using a small molecule approach. Utilizing a 14,400 compound in-silico screen, we identified several small molecules as potential binders to the PEDF interaction interface of LAMR1. From those, we identified a hit compound with anti-proliferative capacity against several prostate cancer cell lines. In PC-3 cells, our hit compound showed activation of anti-tumor signaling and altered proteins associated with prostate cancer and DNA maintenance through LAMR1. We recently tested our hit compound as well as several structural analogs in PC-3 cells at 10 and 50 uM in a cell viability assay to compare the activity of the analogs with that of our hit compound. Several analogs showed activity comparable or superior to our hit compound at 50 uM, with at least a 95% reduction in cell viability after 48 and 96 hours. We are currently working to identify medium-throughput in vitro functional assays that can be utilized for compound screening and profiling. Through an iterative screening, characterization, and optimization process, we hope to identify a lead-type compound to use in future preclinical studies. We are also investigating the mechanism of action downstream of the PEDF/LAMR1 interaction in prostate cancer, which will help us shed light on the therapeutic potential of LAMR1. Support or Funding InformationCTSI Core Grant Purdue Cancer Research Center Department of Basic Medical Sciences Citation Format: Daniel F. Edwards, Charles S. Umbaugh, Marxa L. Figueiredo. A small molecule mimic approach to the PEDF/LAMR1 interaction in prostate 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 LB-267.
Beneficial Effects of Inhibition of Angiotensin-Converting Enzyme on Ischemic Myocardium During Coronary Hypoperfusion in Dogs
Authors: MasafumiKitakaze, TetsuoMinamino, KoichiNode, KazuoKomamura, YoshiroShinozaki, HidezoMori, HiroakiKosaka, MichitoshiInoue, MasatsuguHori, TakenobuKamada
Journal: Circulation (1995)

Background Angiotensin-converting enzyme (ACE) produces angiotensin II, causing vasoconstriction of coronary arteries and reduction of coronary blood flow. The present study was undertaken to test the hypothesis that an ACE inhibitor increases coronary blood flow and improves myocardial metabolic and contractile functions of ischemic myocardium. Methods and Results In 65 open-chest dogs, the left anterior descending coronary artery was perfused through an extracorporeal bypass tube from the left carotid artery. When cilazaprilat (3 μg/kg per minute) was infused into the bypass tube for 10 minutes after reduction of coronary blood flow due to partial occlusion of the bypass tube, coronary blood flow increased from 30±1 to 43±2 mL/100 g per minute despite there being no changes in coronary perfusion pressure (43±1 mm Hg). The ratio of myocardial endocardial flow to epicardial flow increased during an infusion of cilazaprilat. Both fractional shortening and lactate extraction ratio of the perfused area were ...
Relationships of Abdominal Obesity and Hyperinsulinemia to Angiographically Assessed Coronary Artery Disease in Men With Known Mutations in the LDL Receptor Gene
Authors: DanielGaudet, Marie-ClaudeVohl, PatricePerron, GéraldTremblay, ClaudeGagné, DanielLesiège, JeanBergeron, SitalMoorjani, Jean-PierreDesprés
Journal: Circulation (1998)

Background—Patients with a mutation in the LDL receptor gene (familial hypercholesterolemia, or FH) are characterized by substantial elevations in plasma LDL cholesterol and are at higher risk of developing coronary artery disease (CAD). Correlates of abdominal obesity may also contribute to the risk of ischemic cardiac events. Whether the hyperinsulinemic–insulin-resistant state of abdominal obesity affects coronary atherosclerosis among FH patients has not been determined. Methods and Results—The relation of abdominal adiposity and hyperinsulinemia to angiographically assessed CAD was evaluated in a sample of 120 French Canadian men aged <60 years who were heterozygotes for FH and in a group of 280 men without FH. In the present study, the risk of CAD associated with abdominal obesity, as estimated by the waist circumference, was largely dependent on the concomitant variation in plasma lipoprotein and insulin concentrations. In contrast, the association between fasting insulin and CAD was independent of...
Prophylactic and therapeutic inhibition of allergic airway inflammation by probiotic Escherichia coli O83
Authors: Christian Zwicker, Priya Sarate, Mirjana Drinić, Katharina Ambroz, Elke Korb, Ursula Smole, Cordula Köhler, Mark S. Wilson, Hana Kozakova, Peter Sebo, Miloslav Kverka, Ursula Wiedermann, Irma Schabussova
Journal: Journal of Allergy and Clinical Immunology (2018)

GalNAc modification is the prime candidate for a clinically relevant Bet v 1 vaccine.However, the specific design will most likely be dependent on the biophysical and physiologic properties of the individual antigen.The described glycoengineered production platform will be useful for the design of next-generation therapeutic vaccines.
Long-Term Prognosis of Patients With Kawasaki Disease Complicated by Giant Coronary Aneurysms
Authors: KenjiSuda, MotofumiIemura, HiroshiNishiono, YozoTeramachi, YusukeKoteda, ShintaroKishimoto, YoshiyukiKudo, ShinichiItoh, HarukaIshii, TakafumiUeno, TadashiTashiro, MasakiyoNobuyoshi, HirohisaKato, ToyojiroMatsuishi
Journal: Circulation (2011)

Background—Some patients with Kawasaki disease develop giant coronary aneurysms and coronary stenosis, leading to ischemic heart disease. The aim of this study was to determine the long-term prognosis of patients with Kawasaki disease with giant aneurysms. Methods and Results—From our institutional database, 76 patients (57 men and 19 women) who developed giant aneurysms after January 1, 1972, were identified. Information on patient demographics, catheter and surgical interventions, and most recent status was collected from medical charts and patients' contacts. From these data, we calculated the survival rate and cumulative coronary intervention rate. The average age at onset was 2.9±2.9 years, and the median observational period was 19 years. During this period, 7 patients died and 1 patient underwent a heart transplantation, resulting in 95%, 88%, and 88% survival rates at 10, 20, and 30 years after the onset of KD, respectively. On the other hand, catheter and surgical coronary interventions (median, ...
Localized Expression of Aromatase in Human Vascular Tissues
Authors: NobuhiroHarada, HironobuSasano, HiroshiMurakami, TsuneoOhkuma, HiroshiNagura, YasuyukiTakagi
Journal: Circulation Research (1999)

Abstract—The atheroprotective effects of estrogen are well established and the presence of an estrogen receptor in vascular tissues has recently been reported. Therefore, we investigated the localization of the estrogen-producing enzyme aromatase in vascular tissues to assess the possible contribution of endocrine, paracrine, and autocrine modes of action. Aromatase was found in human vascular smooth muscle cells (SMCs) but not in endothelial cells on in situ hybridization. These observations were further supported by quantitative analysis of aromatase mRNA and the activity in 15 human vascular specimens. Only trace levels of expression were detected in the 3 infants examined, whereas 0.0088 to 0.0806 amol/μg RNA of aromatase mRNA and 12.9 to 122.3 fmol · h−1 · mg−1 protein of the activity were detected in 12 of the adult individuals. The switching of tissue-specific exon 1 of the human aromatase gene was also observed in some cases. Aromatase was found to be expressed only in cultured SMCs and not in cul...
Expression of Vascular Endothelial Growth Factor Receptor-2 or Tie-2 on Peripheral Blood Cells Defines Functionally Competent Cell Populations Capable of Reendothelialization
Authors: GrzegorzNowak, AzzaKarrar, CarolinaHolmén, SilviaNava, MehmetUzunel, KjellHultenby, SuchitraSumitran-Holgersson
Journal: Circulation (2004)

Background— Receptor tyrosine kinases that include vascular endothelial growth factor (VEGFR)-1, VEGFR-2, and Tie-2 regulate cardiovascular development and physiological and pathological angiogenesis. We were interested in the phenotypic and functional characterization of peripheral blood cells expressing these receptors and their therapeutic potential in vascular injury. Methods and Results— VEGFR-1+, VEGFR-2+, and Tie-2+ cells constituted ≈3.0±0.2%, 0.8±0.5%, and 2.0±0.3%, respectively, of the total population of mononuclear cells in blood. Phenotypic analysis demonstrated that all 3 cell populations mainly expressed markers of monocytic/macrophage lineage. Only VEGFR-2+ and Tie-2+ cells phenotypically, morphologically, and functionally differentiated to endothelial cells after culture, whereas VEGFR-1+ cells did not. None of the cell types proliferated in vitro. Only freshly isolated VEGFR-2+ or Tie-2+ cells but not VEGFR-2− or Tie-2− cell populations significantly contributed to efficient endotheliali...