tbuckley/cabot-search huggingface dataset:
Abstract 4879: Mutation selectivity of the allosteric SHP2 inhibitor SHP099
Authors: Xiaojun Sun, Yuan Ren, Steven Gunawan, Peng Teng, Zhengming Chen, Harshani R. Lawrence, Jianfeng Cai, Nicholas J. Lawrence, Jie Wu
Journal: Cancer Research (2018)

Abstract SHP2 (PTPN11) mediates oncogenic signaling and gain-of-function (GOF) SHP2 mutations are associated with leukemias and other types of cancer. Recently, SHP099 was identified as a novel allosteric SHP2 inhibitor that displayed high potency and selectivity to the wildtype SHP2 in vitro and inhibited protein tyrosine kinase oncogene-driven cancer cells. However, it was unclear whether SHP099 inhibits SHP2 mutants. Using SHP2 mutant-dependent TF-1 leukemia cells, we determined sensitivities of four common oncogenic SHP2 mutants to SHP099. SHP2D61Y-, SHP2A72V-, and SHP2E76K-expressing TF-1 cells were resistant, whereas SHP2E69K-expressing TF-1 cells were sensitive to SHP099 with a potency similar to that of cytokine-stimulated TF-1 cells expressing the wildtype SHP2. Consistently, SHP099 reduced active ERK1/2 and Bcl-XL and induced apoptosis of SHP2E69K-dependent TF-1 cells, but had no effects on the other SHP2 mutant cell lines. SHP2 knockout cells were unresponsive to SHP099, demonstrating specificity. Like the wildtype SHP2, SHP2E69K PTP was inhibited by SHP099 in vitro with a sub-micromolar IC50, whereas micromolar IC50s of SHP099 were observed against SHP2D61Y, SHP2A72V, and SHP2E76K. These results indicate that SHP2D61Y, SHP2A72V, and SHP2E76K mutants are resistant to SHP099 and that SHP2E69K is a SHP099-sensitive oncogenic mutant. Citation Format: Xiaojun Sun, Yuan Ren, Steven Gunawan, Peng Teng, Zhengming Chen, Harshani R. Lawrence, Jianfeng Cai, Nicholas J. Lawrence, Jie Wu. Mutation selectivity of the allosteric SHP2 inhibitor SHP099 [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 4879.
Abstract 3158: DLL3 regulates migration and invasion of small cell lung cancer
Authors: Megumi Furuta, Jun Konishi Sakakibara, Tetsuaki Shoji, Yuta Takashima, Hajime Kikuchi, Eiki Kikuchi, Junko Kikuchi, Ichiro Kinoshita, Hirotoshi Dosaka Akita, Masaharu Nishimura
Journal: Cancer Research (2018)

Abstract Background: Delta-like protein 3 (DLL3) is a ligand of Notch signaling, which is reported to be a tumor suppressor in small cell lung cancer (SCLC). Previous studies suggest that DLL3 might be associated with neuroendocrine tumorigenesis through inhibition of Notch signaling unlike other activating ligands. Moreover, DLL3 was highly expressed in SCLC, but not in normal lung tissue. However, little is known about function of DLL3 in SCLC. In this study, we examine the effect of DLL3 in tumorigenesis of SCLC. Methods: The mRNA expression levels and proteins of DLL3, Notch receptors (Notch1, Notch2, Notch3 and Notch4), Hes1 and EMT markers (E-cadherin, Snail and Vimentin) were examined using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot in 9 SCLC cell lines (SBC-3, SBC-5, MS-1, RERF-LC-MA, H69, H82, H209, H529 and H1688). We used small interfering RNA (siRNA) to down-regulate the expression of DLL3 in SCLC cell lines. Anchorage-dependent and anchorage-independent cell growth was measured by MTT assay and migration and invasion were assessed by transwell assay. Results: The mRNA of DLL3 was expressed in all of 9 SCLC cell lines. The expression of DLL3 was especially higher in H82, H69, H209, H529 and H1688 cells. Notch1 protein was expressed in SBC-3, SBC-5, MS-1 and H82. Based on DLL3 expression analysis data, we used H82 and H69 in the following experiments. The suppression of DLL3 by siRNA resulted in the moderate inhibition of cell growth of H82 cells in both anchorage-dependent and anchorage-independent cell proliferation. The depletion of DLL3 prevented migration and invasion in the two cell lines. The expressions of Notch1 and Notch target gene, Hes1 were downregulated by DLL3 knockdown in both SCLC cells. Because Notch pathway was reported to regulate EMT, we evaluated the EMT markers when DLL3 was inhibited in SCLC cells. Snail was downregulated in DLL3 knockdown SCLC cells, while protein expression levels of E-cadherin and Vimentin were not changed in these DLL3 knockdown cells compared to control cells. Conclusions: DLL3 promotes the migration and invasion in SCLC cells by modulating Notch1 and Snail. Citation Format: Megumi Furuta, Jun Konishi Sakakibara, Tetsuaki Shoji, Yuta Takashima, Hajime Kikuchi, Eiki Kikuchi, Junko Kikuchi, Ichiro Kinoshita, Hirotoshi Dosaka Akita, Masaharu Nishimura. DLL3 regulates migration and invasion of small cell lung 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 3158.
Association of Remnant Lipoprotein Levels With Impairment of Endothelium-Dependent Vasomotor Function in Human Coronary Arteries
Authors: KiyotakaKugiyama, HidekiDoi, TakeshiMotoyama, HirofumiSoejima, KenjiMisumi, HiroakiKawano, OsamuNakagawa, MichihiroYoshimura, HisaoOgawa, ToshiyukiMatsumura, SeigoSugiyama, TakamitsuNakano, KatsuyukiNakajima, HirofumiYasue
Journal: Circulation (1998)

Background—It remains undetermined whether triglyceride-rich lipoproteins are an independent risk factor for atherosclerosis. Methods and Results—The correlation of responses of coronary arterial diameter (quantitative coronary angiography) and coronary blood flow (intracoronary flow wire technique) to intracoronary infusion of acetylcholine (10 and 50 μg/min) with coronary risk factors including remnant lipoprotein levels was statistically analyzed in 106 consecutive subjects with normal coronary angiograms. Remnant lipoproteins were isolated from fasting blood with an immunoaffinity mixed gel containing anti–apolipoprotein (apo) A-1 and anti–apoB-100 monoclonal antibodies. In multivariate stepwise regression analysis, remnant lipoprotein levels had the most significant correlation with abnormal epicardial coronary vasomotor responses to acetylcholine infusion, reflected by impaired dilation or constriction of the epicardial coronary arteries, and the levels also had an inverse and independent correlatio...
Endothelin-1–Induced Cardiac Hypertrophy Is Inhibited by Activation of Peroxisome Proliferator–Activated Receptor-α Partly Via Blockade of c-Jun NH2-Terminal Kinase Pathway
Authors: YokoIrukayama-Tomobe, TakashiMiyauchi, SatoshiSakai, YoshitoshiKasuya, TakehiroOgata, MasakatsuTakanashi, MotoyukiIemitsu, TatsuhikoSudo, KatsutoshiGoto, IwaoYamaguchi
Journal: Circulation (2004)

Background— Peroxisome proliferator-activated receptor-α (PPAR-α) is a lipid-activated nuclear receptor that negatively regulates the vascular inflammatory gene response by interacting with transcription factors, nuclear factor-κB, and AP-1. However, the roles of PPAR-α activators in endothelin (ET)-1–induced cardiac hypertrophy are not yet known. Methods and Results— First, in cultured neonatal rat cardiomyocytes, a PPAR-α activator, fenofibrate (10 μmol/L), and PPAR-α overexpression markedly inhibited the ET-1–induced increase in protein synthesis. Second, fenofibrate markedly inhibited ET-1–induced increase in c-Jun gene expression and phosphorylation of c-Jun and JNK. These results suggest that this PPAR-α activator interferes with the formation and activation of AP-1 protein induced by ET-1 in cardiomyocytes. Third, fenofibrate significantly inhibited the increase of ET-1 mRNA level by ET-1, which was also confirmed by luciferase assay. Electrophoretic mobility shift assay revealed that fenofibrate s...
Abstract 12930: Low Urine Sodium (UNa) Early After Heart Failure Admission Predicts Long Length of Stay and Early Mortality
Authors: Adriana Luk, John D Groarke, Deepa M Gopal, Emer Joyce, Sachin P Shah, Akshay Desai, Neal Lakdawala, Lynne Stevenson
Journal: Circulation (2015)

Background: Although decongestion is the primary focus of acute heart failure (HF) management, the degree of natriuretic response to diuretic therapy varies and may predict length of stay (LOS) and early outcomes. We hypothesize that a UNa &amp;lt60 mmol/L, measured after initial intravenous (IV) diuretic administration, would be associated with longer duration of IV diuretic, longer LOS, increased use of inotropic therapy in hospital and higher risk of death. Methods and Results: From July 1, 2014-May 30, 2015, we enrolled 100 unique patients hospitalized to the advanced HF service for decompensated HF. Dose of IV diuretic was based on their daily oral home dose. Spot urine samples were collected within a median of 98 (0-187) minutes after initial diuretic therapy. Patients with UNa &amp;lt60 mmol/L (n=30) had significantly lower serum sodium and higher admission NT-proBNP than those with UNa &amp;gt60 mmol/L (n=70). As well, they were more commonly rated with hemodynamic profile C (“cold and wet”, 40.0 vs.11.4%, p=0.002) and INTERMACS profile 3-4 (30.0 vs. 12.9%, p= 0.04). During the hospital stay, patients with low initial UNa required longer use of IV diuretic therapy (9.5 vs. 5.0 days, p&amp;lt0.0001) and had a longer median LOS (12.0 vs. 6.0 days, p&amp;lt 0.0001) than those with high UNa. After adjusting for eGFR, UNa &amp;lt60 mmol/L was still associated with a higher likelihood of inotropic usage in hospital (hazard ratio [HR] 9.91 (3.27-30.05); p&amp;lt0.0001) and death (HR 3.14 (1.20-8.23); p=0.004) at a median follow-up period of 85 (38-159) days (figure 1). Conclusions: Low UNa after initial IV diuretic administration identifies a population of acute HF patients with advanced disease who have longer LOS and are at high risk for death. Measurement of UNa after first diuretic therapy may help to facilitate triage of patients with heart failure and anticipate the need for advanced HF therapies
Abstract 3853: AXL inhibitor promotes anti-tumor immunity through modulation of macrophage polarization
Authors: Shenshen Lai, Qin Xu, Jun Yan, Hong Zhang, Zaihui Zhang
Journal: Cancer Research (2018)

Abstract Polarization of tumor-associated macrophages (TAMs) to classic pro-inflammatory M1 or alternatively activated M2 types plays an important role in establishing tumor microenvironment and determining therapeutic responses. It has become increasingly clear that M2 macrophages contribute to tumor progression by producing anti-inflammatory cytokines and suppressing anti-tumor immunity. AXL receptor tyrosine kinase has recently emerged as a dual therapeutic target in oncology, due to its function in tumor growth, survival and metastasis, as well as immunosuppressive activity. AXL and its ligand Gas6 are both involved in attenuating anti-tumor immune response through modulation of TAM polarization. Thus, targeting the AXL signaling pathway is expected to promote a pro-inflammatory tumor microenvironment, in addition to direct inhibition of tumor growth. SLC-391, a selective small molecule inhibitor for AXL, displays high potency against numerous cancer cell lines through inhibition of AXL/PI3K/AKT-dependent cell proliferation and survival in vitro. Additionally, this compound was also found to alter the cytokine profile expressed in THP1-derived M2 macrophages, including upregulating pro-inflammatory CXCL10 and downregulating anti-inflammatory IL-10. Noticeably, the expression level of AXL was significantly upregulated in THP1-derived macrophages in presence of tumor cell-conditioned medium, which indicated the involvement of AXL in M2 polarization, and therefore strengthening the notion of AXL as a dual therapeutic target. In a co-culture system consisting of THP1-derived macrophages and A549 non-small cell lung cancer cells, SLC-391 targeted AXL activity in both cell types for overall tumor cell suppression through direct and macrophage-mediated inhibition. This observation is supported by inhibition of tumor growth and the increased ratio of M1/M2-polarized TAMs from mice treated with SLC-391 in a CT-26 murine colon carcinoma syngeneic model, considering CT26 cells are not sensitive to SLC-391 in cell-based proliferation assay. In summary, in addition to direct inhibition of tumor cells, SLC-391 also appears to promote anti-tumor immunity through modulation of M2 to M1 transition. Citation Format: Shenshen Lai, Qin Xu, Jun Yan, Hong Zhang, Zaihui Zhang. AXL inhibitor promotes anti-tumor immunity through modulation of macrophage polarization [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 3853.
Abstract 2899: Antitumor activity of CIGB-300, a peptide CK2 inhibitor, in breast cancer models
Authors: Maria F. Gottardo, Carla S. Capibianco, Johanna E. Sidabra, Yasser Perera, Silvio Perea, Daniel F. Alonso, Hernan G. Farina
Journal: Cancer Research (2018)

Abstract CK2 is a serine-threonine kinase that has been involved in growth, proliferation and cell apoptosis. CK2 has a constitutive expression and it has more than 300 substrates. In recent years, CK2 became an interesting target for anticancer therapies. Inhibition of CK2 showed antitumor activity in different types of cancer. Because breast cancer is one of the main tumor types in which CK2 is overexpressed, we focus on the effect of CK2 inhibition as a modulator of key features of breast cancer cell biology. The aim of the present study was to evaluate the role of inhibition of CK2 by CIGB-300 in murine and human mammary carcinoma cell lines. For this purpose, we evaluated the action of CIGB-300 on viability, apoptosis, cell cycle, clonogenic capacity and migration using three different breast tumor cell lines, MCF7 (positive for estrogen, progesterone and HER2-neu receptors), MDA MB 231 (representative of triple negative tumors) and F3II, a murine mammary carcinoma. As compared the potential of CK2 inhibition in these models we included another chemical inhibitor of the enzyme, CX-4945. Our results showed that CIGB-300 reduced the viability of MDA MB 231 (IC50=120 μM) and MCF-7 (IC50=140 μM) (p&amp;lt;0.05, ANOVA). We observed that in both human and murine cell lines CIGB-300 exerts a pro-apoptotic action (TUNEL assay, p&amp;lt;0.05, χ2) and arrest cell cycle. We also found that the inhibition of CK2 by CIGB-300 decreased the clonogenic capacity and migration of F3II, MCF-7 and MDA-MB-231 (p&amp;lt;0.05, ANOVA). In vivo studies using the syngeneic F3II breast cancer model in BalB/c mice showed a decrease in the number of lung metastases in mice treated systemically with CIGB-300 after primary tumor surgery (Mann Whitney test, p&amp;lt;0.05). However, CK2 inhibition did not affect the growth of local recurrences. Also, intravenous administration of CIGB-300 decreased lung metastasis development of F3II cells. These results demonstrate an antimetastatic effect of CIGB-300 in a systemic inoculation model after surgical removal of primary tumors. In this work we demostrated the antitumor effect of CIGB-300 in breast cancer models such as those reported in myeloid leukemia, lung and cervix and head cancer. Citation Format: Maria F. Gottardo, Carla S. Capibianco, Johanna E. Sidabra, Yasser Perera, Silvio Perea, Daniel F. Alonso, Hernan G. Farina. Antitumor activity of CIGB-300, a peptide CK2 inhibitor, in breast cancer models [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 2899.
Abstract 14764: Potential Heterogeneity in the Performance of Carotid Artery Stenting Relative to Carotid Endarterectomy Among Subgroups of Medicare Beneficiaries in Routine Clinical Practice
Authors: Jessica J Jalbert, Louis L Nguyen, Marie D Gerhard-Herman, Lauren A Williams, Chih-Ying Chen, Jun Liu, Hiraku Kumamaru, Andrew T Rothman, John D Seeger, James F Benenati, Peter A Schneider, Herbert D Aronow, Joseph A Johnston, Thomas T Tsai, Christopher J White, Soko Setoguchi
Journal: Circulation (2014)

Introduction: The Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) suggested that the relative performance of carotid artery stenting (CAS) and carotid endarterectomy (CEA) may d...
Effect of Hypercholesterolemia on Expression and Function of Vascular Soluble Guanylyl Cyclase
Authors: UteLaber, ThorstenKober, VerenaSchmitz, AstridSchrammel, WilfriedMeyer, BerndMayer, MartinaWeber, GeorgKojda
Journal: Circulation (2002)

Background— Vasorelaxation to endothelial NO is mediated by activation of soluble guanylyl cyclase (sGC) and impaired by hypercholesterolemia in animals and humans. We investigated whether hypercholesterolemia impacts expression and function of sGC. Methods and Results— White New Zealand rabbits (n=10 per group) received a standard diet for 16 weeks (SD16) (n=20) or 32 weeks (SD32) and a cholesterol diet (7.5 g/kg) for 16 weeks (CD16) (n=20) or 32 weeks (CD32), respectively. Another group received cholesterol diet for 16 weeks followed by standard diet for 16 weeks (CD/SD). Aortic expression of the α1-subunit of sGC (sGC-α1) and β1-subunit of sGC (sGC-β1) was assessed by Western blot. Function was measured by aortic relaxation to S-Nitroso-N-acetyl-D, L-penicillamine (SNAP) and sGC activity in aortic cytosols. Hypercholesterolemia induced an upregulation of sGC-β1 in CD16 (3.5±0.4-fold, P<0.001 versus SD16) and CD32 (4.0±0.4-fold, P<0.001 versus SD32). A similar increase was found for sGC-α1. In striking ...
Abstract 5051: STAT3 signaling activates MSK1-mediated histone H3 phosphorylation inN-nitrosocompounds induced carcinogenesis
Authors: Hongyan Qi, Zhiyi Yang, Shuilian Zhang, Xinxin Ke, Chujun Dai, Jimin Shao, Jing Shen
Journal: Cancer Research (2018)

Abstract Signal transducer and activator of transcription (STATs) signaling, particularly STAT3, have been demonstrated to be one of the central pathways for cancer initiation and progression. However, the functional role of STAT3 in regulation of epigenetic changes in cancer, such as histone modifications, remains unclear. Our present study performed on N-nitroso compounds (NOC) induced gastric epithelial cell transformation revealed a positive correlation of active STAT3 signaling with increased histone H3 phosphorylation. Further analysis showed that mitogen- and-stress activated protein kinase (MSK1) was upregulated by NOC treatment, thereby promoting H3 Ser 10 phosphorylation (H3S10P). Intriguingly, putative STAT3 binding sites were identified in the MSK1 promoter, and we finally confirmed that MSK1 is a novel target gene of STAT3. It has been reported that STAT3 is a direct substrate for MSK1. Therefore, we analyzed the status of STAT3 activation after MSK1 overexpression and knockdown, and a positive feedback loop was found between them. With specific siRNA or inhibitors, we further demonstrated the aberrant activation of STAT3/MSK1/H3S10P axis in MNU-induced gastric cancer (GC) model in mice, human gastric cancer cells, and GC patients. ChIP-seq analysis was performed to determine the H3S10 phosphorylation distribution pattern in NOC-transformed gastric epithelial cells, and some candidate regulated genes were successfully identified. Together, the results of these studies shed light onto a critical role of STAT3 signaling in epigenetic modification network, mediated at least in part by MSK1. Our results suggest that STAT3/MSK1/H3S10P pathway and downstream key effectors represent interesting therapeutic targets in gastric carcinogenesis. Citation Format: Hongyan Qi, Zhiyi Yang, Shuilian Zhang, Xinxin Ke, Chujun Dai, Jimin Shao, Jing Shen. STAT3 signaling activates MSK1-mediated histone H3 phosphorylation in N-nitrosocompounds induced carcinogenesis [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 5051.
Angiogenic Property of Hepatocyte Growth Factor Is Dependent on Upregulation of Essential Transcription Factor for Angiogenesis, ets-1
Authors: NaruyaTomita, RyuichiMorishita, YoshiakiTaniyama, HiromiKoike, MotokuniAoki, HideoShimizu, KunioMatsumoto, ToshikazuNakamura, YasufumiKaneda, ToshioOgihara
Journal: Circulation (2003)

Background— Although hepatocyte growth factor (HGF) is an angiogenic growth factor, it is still unclear how it exerts its angiogenic effects. Thus, we focused on the role of an essential transcription factor for angiogenesis, ets-1. In this study, we addressed the following specific questions: (1) what genes responsible for angiogenesis can be regulated by HGF and (2) whether upregulation of gene expression for angiogenesis is dependent on ets-1. Methods and Results— In human endothelial cells, HGF significantly stimulated the matrix-degrading pathway, such as the production of matrix metalloprotease-1 (MMP-1) through its specific receptor, c-met. In addition, HGF also significantly increased HGF itself and its specific receptor, c-met. Moreover, HGF significantly increased the transcription activity and mRNA expression of ets-1 in a time-dependent manner. Importantly, transfection of antisense ets-1 oligodeoxynucleotides (ODN) resulted in a significant reduction in MMP-1, HGF and c-met. Interestingly, HG...
Essential Role for Prolyl Hydroxylase Domain Protein 2 in Oxygen Homeostasis of the Adult Vascular System
Authors: KotaroTakeda, AnnCowan, Guo-HuaFong
Journal: Circulation (2007)

Background— Prolyl hydroxylase domain (PHD) proteins, including PHD1, PHD2, and PHD3, mediate oxygen-dependent degradation of hypoxia-inducible factor (HIF)-α subunits. Although angiogenic roles of hypoxia-inducible factors are well known, the roles of PHDs in the vascular system remain to be established. Methods and Results— We evaluated angiogenic phenotypes in mice carrying targeted disruptions in genes encoding different PHD isoforms. Although Phd1−/− and Phd3−/− mice did not display apparent angiogenic defects, broad-spectrum conditional knockout of Phd2 led to hyperactive angiogenesis and angiectasia. Blood vessels in PHD2-deficient mice were highly perfusable. Furthermore, examination of medium-sized vessels in subendocardial layer in the heart demonstrated successful recruitment of vascular smooth muscle cells. Surprisingly, increased vascular growth was independent of local efficiency of Phd2 disruption. Mice carrying significant Phd2 disruption in multiple organs, including the liver, heart, kid...