tbuckley/cabot-search huggingface dataset:
Abstract 2538: The interaction of IGFBP3 with HIF2α in the invasion regulation of ovarian epithelial cell cancer
Authors: Ho-Jun Shih
Journal: Cancer Research (2018)

Abstract Ovarian cancer is the most lethal gynecological cancer among women worldwide. The majority of malignant ovarian tumors are epithelial ovarian cancer and metastasis occurred in most patients at the time of diagnosis with worse outcome. New target therapy such as anti-angiogenesis therapy was proved to be effective to prolong progression free survival in epithelial ovarian cancer (EOC) patients. In our previous study, we have established an ovarian endometrioid carcinoma cell line OVTW59. By cDNA microarray analysis and further functional analysis, we have identified Insulin-like Growth Factor Binding Protein-3 (IGFBP-3), Calreticulin (CRT) and Thrombospondin-1(THBS1) correlated with tumor invasion in OVTW59. IGFBP3 and CRT was further found related with poor patient survival outcome. In this study, we focused on the mechanism of IGFBP3 in cancer invasion and metastasis. First we focused on the THBS1 related angiogenesis mechanism which was induced by hypoxia. Through this study, we identified HIF-2α, but not HIF-1α, playing as a significant role in EOC. By q-RT-PCR, Western blotting and immunohistochemical staining, HIF-2α showed opposite expression with IGFBP3, and high IGFBP3 was correlated with high THBS1 expression and low CRT expression. Using other cell lines, the IGFBP3/THBS1/HIF-2α/CRT expression patterns were similar in 293T, H1299 and A549. Furthermore, by Luciferase promoter assay, we verified that IGFBP3 could induce THBS1, inhibit HIF-2α expression, but does not regulate the expression of CRT. IGFBP3 is known as an invasion suppressor gene, THBS1 is an endogeneous inhibitor of angiogenesis, HIF-2α is a regulator of the hypoxia response and angiogenesis inducer, and CRT as a cell adhesion and invasion related protein. Overall, our study shows that IGFBP3 could induce tumor progression and metastasis through direct regulation of THBS1, and HIF-2α and indirect regulation of CRT in EOC. Citation Format: Ho-Jun Shih. The interaction of IGFBP3 with HIF2α in the invasion regulation of ovarian epithelial cell 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 2538.
Intracoronary Autologous Cardiac Progenitor Cell Transfer in Patients With Hypoplastic Left Heart Syndrome
Authors: ShutaIshigami, ShinichiOhtsuki, SuguruTarui, DaikiOusaka, TakahiroEitoku, MaikoKondo, MichihiroOkuyama, JunkoKobayashi, KenjiBaba, SadahikoArai, TakuyaKawabata, KoYoshizumi, AtsushiTateishi, YosukeKuroko, TatsuoIwasaki, ShuheiSato, ShingoKasahara, ShunjiSano, HidemasaOh
Journal: Circulation Research (2015)

Rationale:Hypoplastic left heart syndrome (HLHS) remains a lethal congenital cardiac defect. Recent studies have suggested that intracoronary administration of autologous cardiosphere-derived cells (CDCs) may improve ventricular function. Objective:The aim of this study was to test whether intracoronary delivery of CDCs is feasible and safe in patients with hypoplastic left heart syndrome. Methods and Results:Between January 5, 2011, and January 16, 2012, 14 patients (1.8±1.5 years) were prospectively assigned to receive intracoronary infusion of autologous CDCs 33.4±8.1 days after staged procedures (n=7), followed by 7 controls with standard palliation alone. The primary end point was to assess the safety, and the secondary end point included the preliminary efficacy to verify the right ventricular ejection fraction improvements between baseline and 3 months. Manufacturing and intracoronary delivery of CDCs were feasible, and no serious adverse events were reported within the 18-month follow-up. Patients...
Reduction in Lipopolysaccharide-Induced Thrombocytopenia by Triflavin in a Rat Model of Septicemia
Authors: Joen-RongSheu, Wei-ChungHung, Ching-HsiangWu, Ming-ChiehMa, Ya-ChenKan, Chien-HuangLin, Ming-ShyanLin, Hsiung-NingLuk, Mao-HsiungYen
Journal: Circulation (1999)

Background—Thrombocytopenia frequently occurs early in the course of Gram-negative bacterial infections. Triflavin, an Arg-Gly-Asp–containing disintegrin, has been suggested to interfere with the interaction of fibrinogen with the glycoprotein IIb/IIIa complex. The present study was undertaken to determine whether triflavin could prevent thrombocytopenia in lipopolysaccharide (LPS)-treated rats. Methods and Results—In this study, 51Cr-labeled platelets were used to assess blood and tissue platelet accumulation after LPS challenge. The administration of LPS (4 mg/kg IV bolus) for 4 hours induced a reduction in radiolabeled platelets in blood and an obvious accumulation of platelets in liver. Triflavin (500 μg/kg) but not GRGDS (20 mg/kg) significantly prevented the alteration of radiolabeled platelet distribution in blood and liver when induced by LPS. Furthermore, triflavin but not GRGDS markedly suppressed the elevation in plasma thromboxane B2 concentration within the 4-hour period of LPS administration...
Vesnarinone Prolongs Action Potential Duration Without Reverse Frequency Dependence in Rabbit Ventricular Muscle by Blocking the Delayed Rectifier K+ Current
Authors: JunjiToyama, KaichiroKamiya, JianhuaCheng, Jong-KookLee, RyokoSuzuki, ItsuoKodama
Journal: Circulation (1997)

Background Methanesulfonanilide derivatives, selective inhibitors of the rapidly activating component (IKr) of the delayed rectifier potassium current (IK), prolong action potential duration (APD) of cardiac muscles with reverse frequency dependence, which limits their clinical use because of proarrhythmia. Vesnarinone, a quinolinone derivative developed as a cardiotonic agent, has complex pharmacological properties, but its clinical efficacy is explained in part by IK reduction. Therefore, we investigated the mode of IK block by vesnarinone. Methods and Results IK of the rabbit ventricular myocyte was activated by voltage-clamp steps applied from a holding potential to various depolarizing levels. The development of IK block at depolarization (+10 mV) and its recovery process at hyperpolarization (−75 mV) were compared between vesnarinone and E-4031. The IK block by vesnarinone (3 μmol/L) developed and recovered monoexponentially, with time constants of 361 ms (n=5) and 1.87 seconds (n=4), respectively. ...
Abstract 1985: Upregulation of miR-328 contributes to ovarian cancer stem cell maintenance by downregulating DDB2
Authors: Amit K. Srivastava, Tiantian Cui, Chunhua Han, Ananya Banerjee, Shuri Cai, Lu Liu, Xiaoli Zhang, Zaibo Li, Selvendiran Karuppalyah, Altaf A. Wani, Qi-En Wang
Journal: Cancer Research (2018)

Abstract Cancer stem cells (CSCs) are considered to play a central role in the cancer progression, metastasis and the development of drug resistance. MicroRNAs (miRNAs) have important roles in regulating CSC properties and are considered to be potential therapeutic targets. Diverse aberrantly expressed miRNAs have been reported in ovarian cancer cells. However, there have been few reports about miRNAs that were associated with stemness and progression of ovarian cancer. In this study, miRNA Nanostring profiling analysis was performed to screen crucial miRNAs associated with characteristics and maintenance of CSCs in ovarian cancer. We found that miR-328-3p was remarkably upregulated in ovarian CSCs isolated from both ovarian cancer cell lines and primary ovarian tumors compared to their corresponding bulk cancer cells. We further demonstrated that enforced expression of miR-328-3p in ovarian cancer cell lines expanded the population of ALDH+ cells, enhanced their sphere formation ability, as well as increased their tumorigenicity. While inhibition of miR-328-3p limited the ALDH+ cell population, reduced their sphere formation capacity, and decreased their tumorigenicity. The orthotopic ovarian xenograft assay also demonstrated that inhibition of miR-328-3p impedes tumor growth and metastasis. The mechanistic investigation revealed that repressed ERK1/2 phosphorylation in ovarian CSCs, mainly due to reduced level of reactive oxygen species (ROS), contributes to the enhanced expression of miR-328-3p, and the maintenance of CSCs. Finally, we identified DDB2 as a direct target of miR-328-3p. Given our previous finding that DDB2 is capable of limiting the CSC population in ovarian cancers, we conclude that highly expressed miR-328-3p in ovarian CSCs, probably due to repressed ERK1/2 activity, inhibits DDB2 expression, resulting in the expansion of these CSCs. Thus, targeting miR-328 could be exploited to a novel strategy to eradicate CSCs in ovarian cancer. Citation Format: Amit K. Srivastava, Tiantian Cui, Chunhua Han, Ananya Banerjee, Shuri Cai, Lu Liu, Xiaoli Zhang, Zaibo Li, Selvendiran Karuppalyah, Altaf A. Wani, Qi-En Wang. Upregulation of miR-328 contributes to ovarian cancer stem cell maintenance by downregulating DDB2 [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 1985.
Regular Feeding Plays an Important Role in Cholesterol Homeostasis Through the Liver Circadian Clock
Authors: DaisukeYamajuku, ShingoOkubo, TomonoriHaruma, TakahikoInagaki, YujiOkuda, TomokoKojima, KeijiNoutomi, SeiichiHashimoto, HiroakiOda
Journal: Circulation Research (2009)

Rationale: Peripheral clock control and the relevance of the circadian rhythm to physiology and disease are major questions in mammalian circadian biology. Objective: We examined the physiological functions of the liver clock. Methods and Results: We established a suppressed feeding schedule regimen constituting a high-cholesterol diet delivered every 6 hours without changes in energy and cholesterol intake. We found that rats exposed to this regimen developed hypercholesteremia. In the liver, the rhythmicity of expression of several clock genes was disrupted. Furthermore, the nocturnal expression of the CYP7A1 gene, which encodes the rate-limiting enzyme for the conversion of cholesterol to bile acids, was shifted to a diurnal pattern. Indeed, suppression of a regular feeding rhythm increased the secretion rate of very-low-density lipoprotein cholesterol from the liver and decreased the excretion of fecal bile acids. Conclusions: Our results demonstrated that not only the amount and quality of food but a...
Abstract LB-378: Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing
Authors: Isidro Cortés-Ciriano, June-Koo Lee, Ruibin Xi, Dhawal Jain, Youngsook L. Jung, Lixing Yang, Dmitry Gordenin, Leszek J. Klimczak, Cheng-Zhong Zhang, David S. Pellman, Peter J. Park
Journal: Cancer Research (2018)

Abstract Chromothripsis is a newly discovered mutational phenomenon involving massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in cancer suggest that chromothripsis may be far more common than initially inferred from low resolution DNA copy number data. Here, we analyze the patterns of chromothripsis across 2,658 tumors spanning 39 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of &amp;gt;50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy number states, a considerable fraction of the events involves multiple chromosomes as well as additional structural alterations. In addition to non-homologous end-joining, we detect signatures of replicative processes and templated insertions. Chromothripsis contributes to oncogene amplification as well as to inactivation of genes such as mismatch-repair related genes. These findings show that chromothripsis is a major process driving genome evolution in human cancer. Citation Format: Isidro Cortés-Ciriano, June-Koo Lee, Ruibin Xi, Dhawal Jain, Youngsook L. Jung, Lixing Yang, Dmitry Gordenin, Leszek J. Klimczak, Cheng-Zhong Zhang, David S. Pellman, Peter J. Park. Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing [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-378.
Abstract 2956: Mechanisms of resistance for osimertinib for patients withEGFR-mutant lung cancer: MD Anderson Cancer Center single institution experience with osimertinib resistance
Authors: Xiuning Le, Marcelo Vailati Negrao, Monique Nilsson, Jacqulyne Robichaux, Emily Roarty, Waree Rinsurongkawong, Bonnie Glisson, Jianjun Zhang, John V. Heymach
Journal: Cancer Research (2018)

Abstract PURPOSE: Osimertinib was initially approved for treating epidermal growth factor receptor (EGFR) T790M positive non-small cell lung cancer (NSCLC), and recently is moving forward as the first-line treatment for EGFR sensitizing mutation positive NSCLC. However, the types and frequencies of resistance mechanisms to osimertinib have been incompletely described, and currently there are no guidelines for managing these patients. We evaluated clinical and genetic characteristics of patients who received osimertinib for EGFR-mutant NSCLC. We also provide treatment experience after progression on osimertinib. PATIENTS AND METHODS: Using the MD Anderson Lung Cancer Moon Shot GEMINI database, we identified patients treated with osimertinib and performed clinical outcome analysis. Molecular profiling analysis was performed at the time of progression when available. RESULTS: Eighty two patients were identified. Median PFS on osimertinib was 8.8 months (95% CI, 6.7 to 10.9). Fifty three of the 82 patients had disease progression on osimertinib. Among them, 30 had molecular profiling upon progression. Other than two cases with germline T790M, 11 cases preserved and 17 cases lost T790M mutation. In T790M preserved cases, tertiary mutations of C797S (5 cases) and L792H (2 cases) in EGFR gene, as well as MET amplification (4 cases), were the most common mechanisms of resistance. In T790M lost cases, 12 cases were without known resistance mechanisms. Upon progression, osimertinib was continued in 34 of 51 patients and 17 (50%) of them received local consolidation radiation. The osimertinib continued patients had longer PFS2 compared to the patients who discontinued on osimertinib upon first progression. CONCLUSION: T790M loss is common (61%) in osimertinib resistance cases. In T790M-preserved cases, tertiary mutation within EGFR was the most common mechanism of resistance. MET amplification was observed in both T790M preserved and loss cases. In T790M loss cases, the mechanisms of resistance were mostly EGFR independent, highlighting the importance of understanding T790M-negative resistance mechanisms in the osimertinib era. Citation Format: Xiuning Le, Marcelo Vailati Negrao, Monique Nilsson, Jacqulyne Robichaux, Emily Roarty, Waree Rinsurongkawong, Bonnie Glisson, Jianjun Zhang, John V. Heymach. Mechanisms of resistance for osimertinib for patients with EGFR-mutant lung cancer: MD Anderson Cancer Center single institution experience with osimertinib resistance [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 2956.
Abstract 632A: Microbiome diversity in sputum and circulating exosomes of women with breast cancer and nontuberculous mycobacterial lung disease
Authors: Julie V. Philley, David E. Griffith, Santanu Dasgupta
Journal: Cancer Research (2018)

Abstract The nontuberculous Mycobacterial lung disease, primarily caused by Mycobacterium avium complex is an alarming health problem in the United States and worldwide. Being prevalent among Caucasian women with a history or current diagnosis of breast cancer, Nontuberculous Mycobacterial lung disease poses a significant challenge towards treatment. A large community of resident microbes, including bacteria, virus, Archeas and Fungi living in the human body are being increasingly recognized as the key components of controlling human health and disease. In this study, we examined microbiome diversity in sputa and circulating exosomes derived from women with both breast cancer and nontuberculous Mycobacterial lung disease, women with nontuberculous Mycobacterial lung infection only and healthy women by 16S rDNA sequencing. Our study identified a diverse microbiome community in the sputa and the exosomes dominated by Streptococcus, Haemophillus, Veillonella, Neisseria, Prevotella, Fusobacterium, Bacteroides, Allistipes, Faecalibacterium and Staphylococcus in women with both breast cancer and nontuberculous Mycobacterial lung disease and nontuberculous Mycobacterial lung disease only. Some of these genera, including Fusobacterium, Bacteroides, Allistipes have estrobolome activity and are associated with the development of breast and other neoplasm. This work confirms the presence of a distinct microbiome other than the Mycobacteriome in the sputa and the circulating exosomes of these patients. Further studies investigating the role of the sputa and exosome microbiome linking nontuberculous Mycobacterial pathogenesis and breast cancer are warranted. Citation Format: Julie V. Philley, David E. Griffith, Santanu Dasgupta. Microbiome diversity in sputum and circulating exosomes of women with breast cancer and nontuberculous mycobacterial lung disease [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 632A.
Role for G12/G13 in Agonist-Induced Vascular Smooth Muscle Cell Contraction
Authors: AntjeGohla, GünterSchultz, StefanOffermanns
Journal: Circulation Research (2000)

Abstract—Receptor-induced vascular smooth muscle cell contraction is mediated by dual regulation of myosin light chain (MLC20) phosphorylation through Ca2+-dependent stimulation of myosin light chain kinase and Rho/Rho-kinase–mediated inhibition of myosin phosphatase. Although myosin light chain kinase regulation is initiated by the coupling of receptors to G proteins of the Gq family, Gq and G11, it is not known how receptors regulate the Rho/Rho-kinase–mediated pathway. In vascular smooth muscle cells, receptor-mediated MLC20 phosphorylation and cell contraction was blocked by inhibitors of each of the pathways. Receptors of various vasocontractors were found to couple to Gq/G11 and G12/G13, and constitutively active forms of Gα12 and Gα13 induced a pronounced contraction of vascular smooth muscle cells that could be blocked by C3 exoenzyme, by inhibition of Rho-kinase, and by stable analogues of cGMP and cAMP. Receptor-mediated smooth muscle cell contraction was strongly inhibited by dominant-negative ...
Abstract 14104: Comparisons of Outcomes and Complication Rates Between Elective and Non elective Catheter Ablation for Paroxysmal Supraventricular Tachycardia
Authors: Kanishk Agnihotri, Badal Thakkar, Paris Charilaou, Vishal Goyal, Litsa Lumbrakos, Apurva Badheka, Abhishek Deshmukh, Juan Viles-Gonzalez, Jeffrey Goldberger, Raul Mitrani
Journal: Circulation (2016)

Aim: For patients (pts) with supraventricular tachycardia (SVT), it is unknown whether catheter ablation (CA) complication rates differ in pts during elective vs. non-elective admissions. Methods: ...
Platelet Glycoprotein IIb/IIIa Receptor Blockade Improves Vascular Nitric Oxide Bioavailability in Patients With Coronary Artery Disease
Authors: ThomasHeitzer, IsabelOllmann, KatharinaKöke, ThomasMeinertz, ThomasMunzel
Journal: Circulation (2003)

Background— Platelet glycoprotein IIb/IIIa receptor blockade not only enhances epicardial flow but also improves microvascular perfusion. Inhibition of abnormal platelet–endothelial interactions may contribute to this beneficial effect. The present study was designed to determine whether glycoprotein IIb/IIIa receptor blockade influences endothelial vasomotor function and NO bioactivity in patients with coronary artery disease. Methods and Results— Forty patients with symptomatic coronary artery stenosis were studied before planned percutaneous coronary intervention. By using venous occlusion plethysmography, endothelium-dependent and -independent vasodilation was determined by measuring forearm blood flow responses to acetylcholine with and without NG-monomethyl-l-arginine (L-NMMA) and sodium nitroprusside. Vascular function tests were repeated during glycoprotein IIb/IIIa receptor blockade by tirofiban in 27 patients and by eptifibatide in 13 patients. A subgroup of 10 patients was retested 6 hours afte...
Abstract 3363: <i>PUM3</i> is a triple-negative breast cancer dependency gene that functions in replication fork restart and repair
Authors: Daniel Weekes, Elodie Noel, Callum Walker, Nick Balan, Vandna Shah, Bhavna Sidhu, Anna Pardix, Stephen Pettitt, Christopher J. Lord, Anita Grigoriadis, Tutt N. Andrew
Journal: Cancer Research (2018)

Abstract Triple-Negative Breast Cancers (TNBC) are characterized by high levels of structural chromosome alterations and harbor mutational scars of defects in homologous recombination. Importantly, by acting either as drivers, or as tumor specific dependencies mutated genes in these regions represent potential therapeutic targets In search of such genes we identified that knockdown of the PUM3 gene, which is contained in a 9p24 recurrent ampliicon, impaired the growth of a subset of breast cancer but not mammary epithelial cell lines. Furthermore, the growth defects observed upon PUM3 knockdown in SUM149, a BRCA1 deficient cell line, were reversed by reactivation of BRCA1's function suggesting a BRCA1-deficiency associated dependency. PUM3 knockdown led to an increase in gH2Ax and 53BP1 nuclear foci, impaired restart of stalled replication forks, and decreased RAD51 mediated repair of collapsed replication forks. As a result PUM3 depleted cells have reduced DNA replication rate and slowed cell cycle progression. Knockdown of PUM3 also impaired replication stress induced PARylation and PAR foci formation and PUM3 and PARP1 knockdown showed phenotypic epistasis with respect to cell growth suggesting a potential mechanism for PUM3s replication fork related functions. PUM3 forms a complex with gH2Ax and the replication stalling agent hyroxyurea and PARP-inhibitors increases the nuclear concentration of PUM3. Furthermore PUM3 knockdown increased the sensitivity of breast cancer cells to these agents indicating a role for PUM3 in the repair of lesions generating by these DNA damaging agents. By studying PUM3 we have identified a novel player in replication fork restart and repair whose activity may be particularly relevant in homologous recombination deficient TNBCs. A greater understanding of PUM3's function and the pathways that regulate it may identify novel therapeutic targets for TNBCs. Importantly, direct or indirect modulation of PUM's functions may potentiate the effects of replication stress inducing therapies such as PARP-inhibitors. Citation Format: Daniel Weekes, Elodie Noel, Callum Walker, Nick Balan, Vandna Shah, Bhavna Sidhu, Anna Pardix, Stephen Pettitt, Christopher J. Lord, Anita Grigoriadis, Tutt N. Andrew. PUM3 is a triple-negative breast cancer dependency gene that functions in replication fork restart and repair [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 3363.