tbuckley/cabot-search huggingface dataset:
Abstract 865: Small molecule-mediated modulation of Ras elicits inhibition of phospho ERK signaling through negative feedback on SOS1
Authors: Jennifer E. Howes, Denis T. Akan, Michael C. Burns, Qi Sun, Andrew J. Little, DeMarco V. Camper, Jason R. Abbott, Jason Phan, Taekyu Lee, Olivia W. Rossanese, Alex G. Waterson, Stephen W. Fesik
Journal: Cancer Research (2018)

Abstract Oncogenic mutation of Ras is responsible for more than 30% of all human tumors. Therefore, pharmacological modulation of Ras has attracted great interest as a therapeutic strategy. Our laboratory has recently discovered small molecules that activate Son of Sevenless (SOS)-catalyzed nucleotide exchange on Ras and paradoxically inhibit downstream signaling. Here we describe how pharmacologically targeting SOS1 induces biphasic modulation of Ras-GTP and downstream ERK levels. We consistently observed this phenotype in a variety of cell lines expressing different Ras mutant isoforms, and using multiple chemotypes of compound. In elucidating the molecular mechanism, we observed that compound treatment caused an increase in phosphorylation at ERK consensus motifs on SOS1 that was not observed with the expression of a non-phosphorylatable S1178A SOS1 mutant, or after pre-treatment with an ERK inhibitor. Phosphorylation at S1178 on SOS1 is known to inhibit the association between SOS1 and GRB2 and disrupt SOS1 membrane localization. Consistent with this, we show that wild-type SOS1 and GRB2 dissociated in a time dependent fashion in response to compound treatment, and conversely, this interaction was enhanced with the expression of a S1178A SOS1 mutant. Pre-treatment with an ERK inhibitor prevented compound-induced inhibition of the association between SOS1 and GRB2. Furthermore, in cells expressing either S1178A SOS1 or a constitutively membrane-bound CAAX box tagged SOS1 mutant, we observed elevated Ras-GTP levels over time in response to compound, as compared to the biphasic changes in Ras-GTP exhibited in cells expressing wild-type SOS1. These results show that small molecule agonists of SOS1 cause paradoxical inhibition of Ras-GTP and MAPK signaling in Ras mutant cancer cells, through negative feedback on SOS1. Overall, these compounds provide us with the unique opportunity to better understand the biological functions of SOS and Ras in cancer cells, and may aid in the discovery of small molecules to treat Ras-driven tumors. Citation Format: Jennifer E. Howes, Denis T. Akan, Michael C. Burns, Qi Sun, Andrew J. Little, DeMarco V. Camper, Jason R. Abbott, Jason Phan, Taekyu Lee, Olivia W. Rossanese, Alex G. Waterson, Stephen W. Fesik. Small molecule-mediated modulation of Ras elicits inhibition of phospho ERK signaling through negative feedback on SOS1 [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 865.
Abstract P040: Muscle Metaboreflex Regulation of Arterial Blood Pressure in Children with Congenital Heart Defects
Authors: Corey R Tomczak, Stephanie Fusnik, Elizabeth Hogeweide, Mark J Haykowsky, Michael K Stickland, Shonah Runalls, Ashok Kakadekar, Scott Pharis, Charissa Pockett, Marta Erlandson
Journal: Circulation (2016)

Introduction: Metabolically sensitive afferent fibers in skeletal muscle can signal an increase the sympathetic control of arterial blood pressure during exercise. This process, called the muscle metaboreflex, is augmented in adults with cardiovascular disease and contributes to exercise intolerance. The role of the muscle metaboreflex on blood pressure control in children with congenital heart defects (CHD) is not known. Hypothesis: We tested the hypothesis that the mean arterial pressure (MAP) response to the muscle metaboreflex would be augmented in children with CHD compared to healthy controls. Methods: Twenty-six children with CHD (11±2 years; males=14; females=12) and 21 age- and sex-matched controls (11±3 years; males=10; females=11) were studied. CHD diagnoses included Tetralogy of Fallot (n=7), pulmonary or aortic stenosis (n=3), hypoplastic left or right heart syndrome (n=5), Ebstien’s anomaly (n=1), atrial or ventricular septal defect (n=5), transposition of the great arteries (n=2), double inlet left ventricle (n=1), heart transplantation (n=2), tricuspid or pulmonary atresia (n=2), coarctation of the aorta (n=2), and dilated cardiomyopathy (n=1). Testing included a 3 min rest period followed by isometric handgrip exercise at 30% of maximal voluntary contraction for 2 min. Exercise was followed by 3 min of either a free flow control condition or circulatory occlusion to isolate the muscle metaboreflex. Beat-by-beat MAP was recorded using finger plethysmography. Analyses were completed using mixed designs factorial ANOVA with P &lt; 0.05 as the level of significance. Data are mean ± SD. Results: During the free flow control condition, there was no significant difference in resting MAP (75±9 mmHg vs. 78±9 mmHg), exercise MAP (86±14 mmHg vs. 87±12 mmHg), or free flow MAP (72±10 mmHg vs. 78±9 mmHg) between children with CHD vs. controls, respectively ( P &gt; 0.05). MAP significantly increased from rest to exercise and returned to resting levels during the free flow control condition for both groups. For the circulatory occlusion condition, there was no significant difference in resting MAP (73±11 mmHg vs. 74±8 mmHg), exercise MAP (84±15 mmHg vs. 81±11 mmHg), or circulatory occlusion MAP (79±13 mmHg vs. 79±13 mmHg) between children with CHD vs. controls, respectively ( P &gt; 0.05). MAP significantly increased from rest to exercise and MAP remained elevated above resting levels during circulatory occlusion for both children with CHD and controls ( P &lt; 0.001 for all). Conclusions: Post-exercise circulatory occlusion significantly increases MAP in children with CHD and healthy children, with no significant difference in the magnitude of the MAP response between groups. We conclude that children with CHD demonstrate a normal muscle metaboreflex during post-exercise circulatory occlusion.
A Lamellar Unit of Aortic Medial Structure and Function in Mammals
Authors: Harveywolinsky, Seymourglagov
Journal: Circulation Research (1967)

The close association of elastin, collagen, and smooth muscle in the mammalian aortic media results in viscoelastic properties that account for many of its static and dynamic mechanical features. The structural components of the media are precisely oriented in concentric layers, or lamellar units, of fairly uniform composition. A comparative study of the adult thoracic aorta in 10 mammalian species, including 15 canine breeds, showed that the number of lamellar units in the media of adult mammalian aortas is very nearly proportional to aortic radius regardless of species or variations in measured wall thickness. Estimated wall tensions ranged from 7,820 dynes/cm in a 28-g mouse to 203,000 dynes/cm in a 200,000-g sow, but the average tension per lamellar unit of an aortic media was remarkably constant regardless of species, ranging from 1,090 to 3,010 dynes/cm. The findings suggest that the elastin lamella and the contents of its adjacent interlamellar zone represent the unit of structure and function of t...
Abstract 3278: Performance assessment of de novo assembly-based structural variation detection in the human genome
Authors: Chunlin Xiao
Journal: Cancer Research (2018)

Abstract Structural variations (SVs) contribute to genetic diversity of human populations, affect biologic functions, and cause various human disorders. However, accurately identifying SVs with correct sizes and locations in the human genome remains challenging due to the complexity of the human genome, limitations of sequencing technologies, and drawbacks of analysis methods. The advancement of next-generation sequencing technologies has dramatically decreased the sequencing cost, while substantially increased the lengths of the sequencing reads. Thus, using de novo assembly-based approaches for discovering a full spectrum of SVs in human genome becomes appealing. While various assembly methods have been developed and proposed for general use by the community, the relative efficiency and predictive accuracy of SVs calling based on these assembly methods have not been fully evaluated. In this study, we applied several popular de novo assembly tools to the sequencing read data that were generated using multiple sequencing technologies with technical replicates for NA12878/HG001, a well-studied individual from NIST-led Genome-in-a-Bottle (GIAB) project: a HapMap Caucasian trio and a Chinese Quartet from FDA-led Sequencing Quality Control Phase II (SEQC2) project. Assemblies and SVs callsets were generated for each of the eight samples, and repeatability in the SVs of the technical replicates and reproducibility across sequencing sites were evaluated. The assembly-based SVs callsets have been compared with alignment-based SVs callsets. These results allow better understanding of the impacts of de novo assembly methods on SVs calling, thus providing a better insight to precision medicine. Citation Format: Chunlin Xiao, SEQC2 Working Group #3. Performance assessment of de novo assembly-based structural variation detection in the human genome [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 3278.
Leukotriene C4/D4 Induces P-Selectin and Sialyl Lewisx–Dependent Alterations in Leukocyte Kinetics In Vivo
Authors: SaminaKanwar, BrentJohnston, PaulKubes
Journal: Circulation Research (1995)

Abstract The objective of this study was to assess the effect of leukotriene C4 (LTC4) on the flux of rolling leukocytes, leukocyte rolling velocity, and leukocyte adhesion in postcapillary venules in vivo and to study the underlying molecular mechanisms involved. LTC4 (20 nmol/L) induced a rapid and significant increase in leukocyte rolling flux that was inhibitable by an anti–P-selectin antibody and soluble sialyl Lewisx (sLex). LTC4 also induced a significant reduction in leukocyte rolling velocity, an event that was independent of P-selectin but entirely dependent on sLex. This LTC4-induced reduction in leukocyte rolling velocity was independent of any hemodynamic alterations. Another P-selectin effector, histamine, did not affect leukocyte rolling velocity even at >5000 times the concentration of LTC4. Treatment with an anti–L-selectin antibody had no effect on the LTC4-induced increase in leukocyte rolling or reduction in rolling velocity. Inhibition of LTC4 bioconversion to LTD4 by pretreatment wit...
Abstract 1358: Translational regulation of DNA repair: The mechanism under cap-independent translational regulation of RPA2
Authors: Jia-Jia Cui, Lei-Yun Wang, Ao-Xiang Guo, Ji-Ye Yin
Journal: Cancer Research (2018)

Abstract Purpose: Maintenance of genome integrity is critical for any living cells. A variety of endogenous and exogenous factors can cause DNA damage. RPA2 (Replication protein A2) is a kind of single-stranded DNA binding protein complexes and play an important role in the DNA repair. Internal ribosome entry site (IRES) element is a RNA sequence with a complex structure, the activation of RPA2 IRES element can cause its abnormal expression and finally effects DNA repair pathway. IRES is regulated by eukaryotic translation initiation factors (eIFs) and IRES trans-acting factors (ITAFs). UNR (upstream of N-ras), as one of the important IRES trans-acting factors, and eIF3a (Eukaryotic initiation factor 3a) as one of the important eIFs play important roles in the regulation of RPA2 protein expression via IRES elements. We want to explore the role and potential mechanism of translational regulation of UNR and eIF3a in DNA repair. Methods: In the current study, biotin pull down assay was taken to investigate the interaction between RPA2 IRES and UNR. Western blot and qPCR were used to detect protein and mRNA level respectively. CO-IP assay were conducted for interaction of eIF3a with UNR. Immunofluorescence assay was taken to investigate the intracellular localization of UNR and eIF3a, as well as the regulation of UNR on DNA double strand break repair pathway. GST pull down assay was carried out to further identify the interaction between two proteins. Electrophoretic mobility shift assay was carried out to explore the domains of UNR and eIF3a that bind to RPA2 IRES element. Dual-luciferase reporter assay, comet assay and immunofluorescence assay were used to investigate the DNA repair pathway activity. Results: UNR and eIF3a translationally regulate RPA2 by combining with RPA2 IRES. It was found that the expression of RPA2 was down-regulated by UNR with no change on mRNA level. We further found that UNR combined with RPA2 IRES via CSD1 domain. And no domains of eIF3a bind to RPA2 IRES RNA.Meanwhile, the location of UNR and eIF3a was consistent. A series of assays indicate that CSD1 domain of UNR bind to PCI domain of. RPA2 play an important role in the DNA repair. We found that UNR down-regulated double-strand break repair (DSB) activity and nucleotide excision repair (NER) activity. Conclusion: UNR and eIF3a can regulate the expression of RPA2 on translational level, and further regulate the activity of DNA repair, which may reveal the potential mechanism of translational regulation and DNA repair. Citation Format: Jia-Jia Cui, Lei-Yun Wang, Ao-Xiang Guo, Ji-Ye Yin. Translational regulation of DNA repair: The mechanism under cap-independent translational regulation of RPA2 [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 1358.
Abstract 4731: Contribution of FcγRIIB to creating the suppressive tumor microenvironment
Authors: Yuki Kasahara, Hidekazu Shirota, Chikashi Ishioka
Journal: Cancer Research (2018)

Abstract Various immune cells are recruited in tumor microenvironment. It is well established that cellular immune responses, such as cytotoxic or suppressive activities play an important role in regulating tumor growth and metastasis. However, contribution of humoral immune responses against tumor is incompletely understood. The Fc receptors constitute critical elements for activating or down-regulating immune responses through immunoglobulin immune complex. Here, we examined the potential role of inhibitory Fc receptor, Fc gamma RIIb in tumor immunity using mice model. Current findings indicate that tumor-specific antibodies are induced and control tumor immunity. Deletion of Fc gamma RIIb receptor significantly improves both cellular and humoral anti-tumor immunity, delays tumor growth. These findings indicate that spontaneous antibody against tumor create the suppressive tumor microenvironment through Fc gamma RIIb signaling, and suggests attractive therapeutic target for cancer immunotherapy. Citation Format: Yuki Kasahara, Hidekazu Shirota, Chikashi Ishioka. Contribution of FcγRIIB to creating the suppressive tumor microenvironment [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 4731.
Direct Evidence for Increased Hydroxyl Radicals Originating From Superoxide in the Failing Myocardium
Authors: TomomiIde, HiroyukiTsutsui, ShintaroKinugawa, NobuhiroSuematsu, ShunjiHayashidani, KazuhiroIchikawa, HideoUtsumi, YoujiMachida, KensukeEgashira, AkiraTakeshita
Journal: Circulation Research (2000)

Abstract—Experimental and clinical studies have suggested an increased production of reactive oxygen species (ROS) in the failing myocardium. The present study aimed to obtain direct evidence for increased ROS and to determine the contribution of superoxide anion (·O2−), H2O2, and hydroxy radical (·OH) in failing myocardial tissue. Heart failure was produced in adult mongrel dogs by rapid ventricular pacing at 240 bpm for 4 weeks. To assess the production of ROS directly, freeze-clamped myocardial tissue homogenates were reacted with the nitroxide radical, 4-hydroxy-2,2,6,6,-tetramethyl-piperidine-N-oxyl, and its spin signals were detected by electron spin resonance spectroscopy. The rate of electron spin resonance signal decay, proportional to ·OH level, was significantly increased in heart failure, which was inhibited by the addition of dimethylthiourea (·OH scavenger) into the reaction mixture. Increased ·OH in the failing heart was abolished to the same extent in the presence of desferrioxamine (iron ...
Abstract 3687: Dot1l inhibition selectively impairs androgen receptor dependent prostate cancer growth through loss of telomere integrity
Authors: Rajita Vatapalli, Yara Rodriguez, Changsheng Zhao, Vinay Sagar, Jonathan Anker, Sahithi Pamarthi, Kenji Unno, Benedito Carneiro, Debabrata Chakravarti, Sarki Abdulkadir
Journal: Cancer Research (2018)

Abstract The histone methyltransferase DOT1L methylates lysine 79 (K79) on histone H3 and this histone mark is associated with activation of gene expression. DOT1L has a well-known role in MLL fusion leukemogenesis, however, its role in prostate cancer is yet to be elucidated. Here we show that DOT1L is overexpressed in many solid tumors including prostate cancer and is associated with a poor outcome. Genetic and chemical targeting of DOT1L showed a preferential loss in cell viability and colony formation in androgen receptor (AR)-signaling competent prostate cancer cells, including castration-resistant and enzalutamide-resistant cells. DOT1L inhibition reduced AR levels and upregulated enzymes involved in testosterone catabolism but only affected the expression of a subset of AR target genes. More importantly, loss of DOT1L selectively impaired telomere integrity by promoting telomere uncapping and shortening in AR-signaling competent cells. DOT1L inhibition also reduced the expression of telomerase and Shelterin complex genes including TRF2 and POT1. Recruitment of AR to telomeres and K79 methylation at sub-telomeric regions was also diminished. Consequently, loss of DOT1L leads to induction of Telomere dysfunction induced foci (TIF) and activates a cellular senescence program in these cells. Hence, these results provide compelling evidence for DOT1L inhibition as a novel therapeutic approach in advanced prostate cancers. Citation Format: Rajita Vatapalli, Yara Rodriguez, Changsheng Zhao, Vinay Sagar, Jonathan Anker, Sahithi Pamarthi, Kenji Unno, Benedito Carneiro, Debabrata Chakravarti, Sarki Abdulkadir. Dot1l inhibition selectively impairs androgen receptor dependent prostate cancer growth through loss of telomere integrity [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 3687.
Current time-to-positivity of blood cultures in febrile neutropenia: a tool to be used in stewardship de-escalation strategies
Authors: P. Puerta-Alcalde, C. Cardozo, M. Suárez-Lledó, O. Rodríguez-Núñez, L. Morata, C. Fehér, F. Marco, A. Del Río, J.A. Martínez, J. Mensa, M. Rovira, J. Esteve, A. Soriano, C. Garcia-Vidal
Journal: Clinical Microbiology and Infection (2018)
Arterial Endothelium-Specific Activin Receptor-Like Kinase 1 Expression Suggests Its Role in Arterialization and Vascular Remodeling
Authors: TsugioSeki, JihyeYun, S. PaulOh
Journal: Circulation Research (2003)

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by epistaxis, mucocutaneous telangiectases, and arteriovenous malformations (AVM). Two genes are linked to HHT: endoglin (ENG) in HHT1 and activin receptor-like kinase 1 (ACVRL1; ALK1) in HHT2. Although both genes are involved in the transforming growth factor β signaling pathways, the pathogenetic mechanisms for HHT remain elusive. It was shown that mutations in the Alk1 gene in mice and zebrafish resulted in an embryonic lethal phenotype due to severe dilation of blood vessels. We created a novel null mutant mouse line for Alk1 (Alk1lacZ) by replacing its exons, including the one that encodes the transmembrane domain, with the β-galactosidase gene. Using Alk1lacZ mice, we show that Alk1 is predominantly expressed in developing arterial endothelium. Alk1 expression is greatly diminished in adult arteries, but is induced in preexisting feeding arteries and newly forming arterial vessels during wound healin...
Abstract A09: Rational combinational therapy with PARP and BRD4 inhibitor in ovarian cancer
Authors: Chaoyang Sun, Jun Yin, Yong Fang, Gordon B. Mills
Journal: Clinical Cancer Research (2018)

Abstract Poly(ADP-ribose) polymerase inhibitors (PARPi) are selectively active in cells with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1/2 and other pathway members. We thus sought small-molecule inhibitors that induce HRD in HR competent cells to identify approaches to induce synthetic lethality with PARPi and extend the utility of PARPi. We demonstrate that inhibition of bromodomain containing 4 (BRD4) induces HRD and sensitizes cells across multiple tumor lineages to PARPi regardless of BRCA1/2, TP53, RAS, or BRAF status. Note: This abstract was not presented at the conference. Citation Format: Chaoyang Sun, Jun Yin, Yong Fang, Gordon B. Mills. Rational combinational therapy with PARP and BRD4 inhibitor in ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A09.