tbuckley/cabot-search huggingface dataset:
Critical Role of Bone Marrow Apoptosis-Associated Speck-Like Protein, an Inflammasome Adaptor Molecule, in Neointimal Formation After Vascular Injury in Mice
Authors: NoriyukiYajima, MasafumiTakahashi, HajimeMorimoto, YujiShiba, YasukoTakahashi, JunyaMasumoto, HirohikoIse, JunjiSagara, JunNakayama, Shun'ichiroTaniguchi, UichiIkeda
Journal: Circulation (2008)

Background— Inflammatory cytokines such as interleukin (IL)-1β and IL-18 play an important role in the development of atherosclerosis and restenosis. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an adaptor protein that regulates caspase-1–dependent IL-1β and IL-18 generation; however, the role of ASC in vascular injury remains undefined. Here, we investigated the contribution of ASC to neointimal formation after vascular injury in ASC-deficient (ASC−/−) mice. Methods and Results— Wire-mediated vascular injury was produced in the femoral artery of ASC−/− and wild-type mice. Immunohistochemical analysis revealed that ASC was markedly expressed at the site of vascular injury. Neointimal formation was significantly attenuated in ASC−/− mice after injury. IL-1β and IL-18 were expressed in the neointimal lesion in wild-type mice but showed decreased expression in the lesion of ASC−/− mice. To investigate the contribution of bone marrow–derived cells, we developed bone...
Abstract 19565: The Safety and Efficacy of Platelet Glycoprotein Iib Iiia Antagonist by Intracoronary Administration versus Intravenous Administration in Patients With St Segment Elevation Myocardial Infarction: A Meta-analysis
Authors: Jun Pang, Zheng Zhang, Tongzhang Zheng, Ming Bai, YU PENG, xingbin Liu, xingbin Liu, Mao Cheng
Journal: Circulation (2015)

Objective: Evaluate the administration (IC) and intravenous(IV) administration of platelet glycoprotein IIb / IIIa antagonist in STEMI patients. Methods: We searched PubMed, EMBASE, Web of Science, the Chinese Biomedical Medical Literature database, and the Cochrane Library, the retrieval time is May 2015. The papers which compared the safety and efficacy of IC and IV STEMI patients with platelet glycoprotein IIb / IIIa antagonist were included.Two researchers evaluated the trails and collected data according to 5.0.2 Cochrane Handbook. The data were merged by RevMan 5.0 software. Results: Finally we included 17 RCTs(n=8279, including 4260 IC administration patients, and 4019 IV administration patients). The GP IIb / IIIa antagonist was injected in the coronary after stent releasing during PCI in the IC group. Meta analysis showed: In the STEMI trials, intracoronary group had better clinical outcomes than intravenous group in the following index: short time MACE (one month after PCI) [OR=0.47,95%CI:0.23-0.97], congestive heart failure [OR=0.59,95%CI:0.41-0.84], left ventricular ejection fraction [MD=1.11, 95%CI: 0.48-1.74], infarct size [MD=-1.00, 95%CI: -1.65~ -0.35], myocardial blush grade 3 [OR=1.60, 95%CI: 1.12-2.27], drug occupational rate [OR=4.16, 95%CI: 1.45-11.92], wall motion score index[MD=-0.27,95%CI: -0.51~ -0.03]. And the IC and IV group were similar in the death, long time MACE(1 year after PCI), stent thrombosis, sever bleeding, ST-segment resolution -1 month after PCI, target vessel revascularization, myocardial infarction recurrence, TIMI grade 3 after PCI, left ventricular end systolic volume, left ventricular end diastolic volume, intervention success rate, life threatening arrhythmia, stroke after PCI, CK-MB, operation time, E/ A, cardiac death, minor bleeding, with no significant difference (P&gt; 0.05). Conclusions: This updated meta-analysis shows, compared to the IV, IC administration of platelet glycoprotein IIb / IIIa antagonist could reduce the risk of short time MACE (one month after PCI), congestive heart failure, and improve left ventricular ejection fraction, so IC administration of platelet glycoprotein IIb / IIIa antagonist could be a considerable way to be used in STEMI patients.
Noradrenergic Vascular Hyper-Responsiveness in Human Hypertension Is Dependent on Oxygen Free Radical Impairment of Nitric Oxide Activity
Authors: GiuseppeLembo, CarmineVecchione, RaffaeleIzzo, LuigiFratta, DarioFontana, GennaroMarino, GiovanniPilato, BrunoTrimarco
Journal: Circulation (2000)

Background—Noradrenergic vascular hyper-responsiveness is a hallmark of essential hypertension. To evaluate whether nitric oxide plays a role in the enhanced vascular response to norepinephrine in hypertension, we examined 32 hypertensives and 28 normotensives who were distributed in 3 experimental series. Methods and Results—In the first series, we measured the forearm blood flow (FBF) response to a norepinephrine infusion under control conditions and during the infusion of l-N-monomethylarginine (L-NMMA). Norepinephrine evoked dose-dependent vasoconstriction that was greater in hypertensives than in normotensives (maximum FBF, −61±1 versus −51±1%; P<0.01). During L-NMMA infusion, norepinephrine vasoconstriction was not modified in hypertensives; however, it was potentiated in normotensives (maximum FBF, −64±2%; P<0.01). In the second series, we tested whether norepinephrine vasoconstriction could be affected by an antioxidant such as ascorbic acid. Norepinephrine vasoconstriction was blunted by ascorbic...
Long non-coding RNA H19 regulates endothelial cell aging via inhibition of STAT3 signalling
Authors: Patrick Hofmann, Janina Sommer, Kosta Theodorou, Luisa Kirchhof, Ariane Fischer, Yuhuang Li, Ljubica Perisic, Ulf Hedin, Lars Maegdefessel, Stefanie Dimmeler, Reinier A Boon
Journal: Cardiovascular Research (2018)

Abstract Aims Long non-coding RNAs (lncRNAs) have been shown to regulate numerous processes in the human genome, but the function of these transcripts in vascular aging is largely unknown. We aim to characterize the expression of lncRNAs in endothelial aging and analyse the function of the highly conserved lncRNA H19. Methods and results H19 was downregulated in endothelium of aged mice. In human, atherosclerotic plaques H19 was mainly expressed by endothelial cells and H19 was significantly reduced in comparison to healthy carotid artery biopsies. Loss of H19 led to an upregulation of p16 and p21, reduced proliferation and increased senescence in vitro. Depletion of H19 in aortic rings of young mice inhibited sprouting capacity. We generated endothelial-specific inducible H19 deficient mice (H19iEC-KO), resulting in increased systolic blood pressure compared with control littermates (Ctrl). These H19iEC-KO and Ctrl mice were subjected to hindlimb ischaemia, which showed reduced capillary density in H19iEC-KO mice. Mechanistically, exon array analysis revealed an involvement of H19 in IL-6 signalling. Accordingly, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 were upregulated upon H19 depletion. A luciferase reporter screen for differential transcription factor activity revealed STAT3 as being induced upon H19 depletion and repressed after H19 overexpression. Furthermore, depletion of H19 increased the phosphorylation of STAT3 at TYR705 and pharmacological inhibition of STAT3 activation abolished the effects of H19 silencing on p21 and vascular cell adhesion molecule 1 expression as well as proliferation. Conclusion These data reveal a pivotal role for the lncRNA H19 in controlling endothelial cell aging.
Abstract 18650: Extracellular Vesicle-associated miRNAs Induce Innate Immune Response in Sepsis
Authors: Jinjin Xu, Lin Zou, Yan Feng, Olivia Conn, Wei Chao
Journal: Circulation (2017)

Introduction: We have recently reported that a group of host cellular microRNAs (miR-34a, -122, - 145, -146, -210) are released into the circulation during severe sepsis and that their synthetic mi...
Abstract 4465: Variants of uncertain significance of the cancer-predisposing genes in two thousand Japanese whole-genome sequencing data
Authors: Jun Yasuda, Keita Iida, Kazuki Kumada, Soichi Ogishima, Yusuke Shibuya, Hideki Tokunaga, Nobuo Yaegashi
Journal: Cancer Research (2018)

Abstract Many of the cancer predisposing genes are known to be associated with juvenile cancer syndromes such as Li Fraumeni syndrome. The responsible variants of the juvenile cancer syndromes are usually very deleterious and show strong biological effects on the gene functions. It is not so easy to estimate the clinical significance of the moderately deleterious variants in those genes that may have intermediate effects on the hosts' cancer predisposition and these moderately deleterious (or hypomorphic) variants are now classified as variants of uncertain significance (VUSs). The insight that VUSs may have moderate but clinically significant effects on cancer susceptibility now attracts cancer geneticists. To elucidate the state of VUSs of 135 cancer predisposing genes in general population, we functionally annotate the single nucleotide variants (SNVs) in the genes from a 2049 whole genome sequence high confident dataset (2KJPN-HC) obtained from participants in a genome cohort by Tohoku Medical Megabank Organization. Frequency spectrum of the Combined Annotation-Dependent Depletion (CADD) scores of the 135 genes showed very similar pattern to the whole 2KJPN-HC and a weak negative correlation (r = -0.0579) is observed between allele frequencies and CADD scores for each SNV. Among the variants found in 2KJPN, some of the variants are considered as responsible for hereditary cancer syndromes. We used the CADD and Eigen, other scoring system for estimation of impact of the variants, for the known damaging variants in the BRCA1 and BRCA2 genes to narrow down the candidate VUSs that may have moderate risks for cancer predisposition and found one VUS that is identified as a moderate risk SNP for breast cancer in the other studies. Combination of CADD and Eigen will be useful to narrow down the candidate deleterious SNVs for cancer predisposition. Citation Format: Jun Yasuda, Keita Iida, Kazuki Kumada, Soichi Ogishima, Yusuke Shibuya, Hideki Tokunaga, Nobuo Yaegashi. Variants of uncertain significance of the cancer-predisposing genes in two thousand Japanese whole-genome sequencing data [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 4465.
Abstract 1503: Arsenic trioxide inhibits proliferation of acute leukemia cells through reduced expression of E2F1, cyclin E, and activation of retinoblastoma protein
Authors: Sanjay Kumar, Paul Tchounwou
Journal: Cancer Research (2018)

Abstract Arsenic trioxide (ATO) is has been used successfully in the treatment of all age group of acute promyelocytic leukemia (APL) patients in both induction and consolidation therapy. It inhibits growth APL cells through various mechanism including oxidative stress, cell cycle regulation, and apoptosis. However, detail molecular mechanism ATO-induced APL cell proliferation inhibition mostly poorly known. E2F1, a transcriptional factor widely involved proliferation and differention of many types of cancer cells through providing signal to accumulation p53, cell cycle regulation, and apoptosis. We hypothesized that ATO inhibits proliferation and differentiation of APL cells through reduced expression of E2 F1, cyclin E and stimulation of retinoblastoma and AMPKα2 expressions in APL cells. To test hypothesis, we used APL cell lines and after treatment with different concentration (2,4,6, and 8μg/ml) ATO, checked expression level of E2F1, cyclin A, cyclin E, Akt, retinoblastoma (Rb D20 &amp; H1) and AMPKα2 by western blotting, immunocytochemistry, and confocal imaging. We found that it reduced expression significantly of E2F1, cyclin E by modulating expression profile of retinoblastoma (Rb D20 &amp; H1), Akt and AMPKα2 proteins in APL cells concentration dependent manner. Our data showed that E2F1 associated with p53 and its association may involve ATO -induced cell cycle regulation and apoptosis. On the basis of these findings, we conclude that ATO inhibits APL cells proliferation by reducing E2F1, cyclin E expression through stimulation of retinoblastoma (Rb D20 &amp; H1), Akt , and AMPKα2 proteins. It is novel mode of action of ATO in APL cells and may help in the designing of new anti-leukemic drugs for treatment of APL patients more efficiently and quickly. Keywords: Arsenic trioxide, E2F1, cyclin E, Rb proteins, AMPKα2, and APL cells. Acknowledgements: This research was financially supported by National Institutes of Health NCRR Grant No. 5G12RR013459 and MIMHD Grant No. 8G12MD007581, through the RCMI-Center for Environmental Health at Jackson State University. Citation Format: Sanjay Kumar, Paul Tchounwou. Arsenic trioxide inhibits proliferation of acute leukemia cells through reduced expression of E2F1, cyclin E, and activation of retinoblastoma protein [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 1503.
Abstract 15125: Percutaneous Transluminal Pulmonary Angioplasty Improves Hemodynamics and Right Ventricular Function in Patients with Chronic Thromboembolic Pulmonary Hypertension -One Year Follow-up Study
Authors: Masanobu Miura, Koichiro Sugimura, Kotaro Nochioka, Tatsuo Aoki, Shunsuke Tatebe, Saori Yamamoto, Nobuhiro Yaoita, Haruka Sato, Kimio Sato, Hiroaki Shimokawa
Journal: Circulation (2014)

Objectives: Right ventricular function (RV) is an important prognostic indicator of pulmonary hypertension. Recent studies have demonstrated that percutaneous transluminal pulmonary angioplasty (PTPA) improves pulmonary hemodynamics in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). In this study, we examined whether PTPA also improves right ventricular dysfunction in those patients. Methods: We performed a total of 252 PTPA procedures (median 4 procedures per patient) for 56 consecutive patients with inoperable CTEPH, after stabilizing their condition using conventional pulmonary vasodilators. Among them, we enrolled 33 patients who had finished 1-year follow-up after final PTPA in the present study (female 81.8%, median age 60 yrs.). RV function was evaluated by tricuspid annular plane systolic excursion (TAPSE) on echocardiogram (42.4%, n=14) and RV ejection fraction (RVEF) on cardiac magnetic resonance imaging (39.4%, n=13) before and after PTPA. Results: No patient died during the PTPA procedure or during the 1-year follow-up period. Comparisons before and after PTPA showed marked improvement of WHO functional class III/IV (75.7 to 0%, P&lt;0.001), 6-min walking distance (316 to 480 m, P&lt;0.001), and brain natriuretic peptide level (93 to 23 pg/ml, P&lt;0.001) and significant hemodynamic improvements for mean pulmonary artery pressure (42.3±10.7 to 24.4±5.7mmHg, P&lt;0.001), cardiac index (2.2±0.6 to 2.7±0.6 L/min•m2, P&lt;0.001) and pulmonary vascular resistance (786±384 to 265±93 dyn•sec•cm5, P&lt;0.001). Furthermore, RV function was also significantly improved for both TAPSE (18.0±4.0 to 23.4±4.3mm, P&lt;0.001) and RVEF (37.9±11.0 to 52.4±7.1%, P&lt;0.001) (Figure). Conclusions: PTPA improves not only pulmonary hemodynamics but also RV function in patients with inoperable CTEPH.
Thrombosis Increases Circulatory Hepatocyte Growth Factor by Degranulation of Mast Cells
Authors: MakotoKinoshita, TadashiMiyamoto, NaohiroOhashi, ShigetakeSasayama, AkiraMatsumori
Journal: Circulation (2002)

Background— Plasma concentrations of hepatocyte growth factor (HGF), a powerful angiogenic growth factor inducible by heparin, increase in thrombus-associated disorders such as myocardial infarction and unstable angina. The mechanism of this thrombus-associated HGF release, however, is unknown. Methods and Results— Wistar rats received through the tail vein (1) normal saline (NS), (2) 50 μg of the mast cell–degranulating agent CP48/80, or (3) 1000 U/kg heparin. Blood samples were collected at 10 minutes or 30 minutes after the injections, or from untreated rats, for measurements of HGF. The same experiments were performed in mast cell–deficient white spotting (Ws) rats. Ws rats have a small deletion of the c-kit gene and are deficient in mast cells. Intravenous heparin immediately increased plasma HGF in both Wistar (38.02±2.08 ng/mL versus 1.11±0.70 ng/mL in untreated rats, P<0.0001) and Ws rats (36.39±4.15 ng/mL versus 0.66±0.18 ng/mL in NS-treated rats, P<0.0001). Injection of CP48/80 also increased pl...
Abstract 2154: A potent and orally available tubulin inhibitor ABI-231 suppresses triple negative breast cancer tumor growth and metastasis
Authors: Shanshan Deng, Raya Krutilina, Qinghui Wang, Tiffany N. Seagroves, Duane D. Miller, Wei Li
Journal: Cancer Research (2018)

Abstract Triple-negative breast cancer (TNBC) is the most aggressive type and accounts for at least 15% of all types of breast cancer in the USA. TNBC is defined as tumors that lack the expression of estrogen receptor, progesterone receptor and human epithermal growth factor 2, and it is always characterized by poor prognosis due to the lack of molecular targets and the rapid development of resistance to many chemotherapeutic drugs. Interfering with microtubule dynamics is a validated drug target. Currently, one of the standard cares for TNBC treatment is using taxanes based chemotherapy, such as paclitaxel, which targets microtubules. However, drug resistance and neurotoxicities often limit their clinical efficacy, thus there are continuous needs to develop more effective therapies that could overcome these clinical limitations. In this study, we evaluated the preclinical efficacy of our potent tubulin inhibitor, ABI-231, in treating TNBC in mouse xenograft models. ABI-231 inhibited tubulin polymerization and effectively overcame P-gp mediated multidrug resistance, and it is orally available. ABI-231 showed remarkable anticancer activities against two TNBC cell lines at low nanomolar concentrations, and it could inhibit the cancer cell colony formation. Treatment with ABI-231 suppressed invasion and migration of TNBC cells, and significantly induced apoptosis of TNBC cells in vitro. ABI-231 inhibited TNBC tumor growth in a dose-dependent manner without acute toxicity in an orthotopic TNBC xenograft model. ABI-231 had similar efficacy to that of paclitaxel as tested in this mouse model. In addition, ABI-231 significantly reduced metastasis of TNBC in a tail vein mouse model. Collectively, these preliminary studies strongly suggest that ABI-231 is potent to inhibit the growth and metastasis of TNBC both in vitro and in vivo, and this potent tubulin inhibitor is a promising drug candidate for the more effective treatment of TNBC. Supported by NIH grant R01CA148706. Citation Format: Shanshan Deng, Raya Krutilina, Qinghui Wang, Tiffany N. Seagroves, Duane D. Miller, Wei Li. A potent and orally available tubulin inhibitor ABI-231 suppresses triple negative breast cancer tumor growth and metastasis [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 2154.
Onset of Angina Pectoris in Relation to Circulatory Adaptation during Arm and Leg Exercise
Authors: Johnwahren, Stellanbygdeman
Journal: Circulation (1971)

The circulatory adaptation to arm and leg exercise was studied with stepwise increased work loads in 10 patients with signs of coronary artery disease. Both arm and leg exercise elicited angina pectoris in all patients. Anginal pain appeared at the same level of pressure-time per minute (PTM) in the two forms of exercise, but at a smaller work load and a lower pulmonary oxygen uptake during arm exercise than during leg exercise. Heart rate, PTM, and peak systolic, systolic mean, diastolic, and mean arterial pressures all increased more steeply in relation to work load during arm exercise than during leg exercise. The differences in circulatory adaptation during arm and leg exercise are attributed in part to a lower mechanical efficiency and a higher sympathetic outflow during arm exercise. These factors may in turn reflect the involvement of smaller muscle groups and a larger component of static work with trunk muscles during arm exercise. The pattern of response to exercise resembles that seen in healthy...
Abstract 649: Development of a novel RNA sequencing approach that identifies aberrant splicing in cancer predisposing genes
Authors: Anne M. Jansen, Heleen M. van der Klift, Jaap D. van Eendenburg, Carli M. Tops, Juul T. Wijnen, Frederik J. Hes, Ajay Goel, Hans Morreau, Tom van Wezel
Journal: Cancer Research (2018)

Abstract Background: High-throughput sequencing efforts in molecular tumor diagnostics detect increased numbers of novel genetic variants, including the ones that are predicted to affect splicing. Current approach for predicting whether a specific variant may result in aberrant RNA transcripts often consists of in-silico prediction using bioinformatics prediction tools, which is sometimes followed by RT-PCR analysis of the RNA extracted from blood, or functional splicing reporter assays. Although high-quality patient RNA analysis is usually preferred, such RNA is not always available, or the analysis is hampered due to degradation of aberrant transcripts through nonsense-mediated decay. To overcome this issue, we investigated the possibility of analyzing RNA isolated from formalin-fixed paraffin-embedded (FFPE) tissues, with the underlying hypothesis that formalin fixation may inhibit RNA degradation, enabling the detection of aberrant RNA products. Methods: RNA analysis was performed for 13 canonical splice site variants predicted or known to affect splicing in the cancer predisposition genes MLH1, MSH2, MSH6, APC and BRCA1. Of 11 variants, total nucleic acid was obtained from FFPE tumor tissues. For two variants, no FFPE material was available, but EBV-transformed B-cells carrying a splice variant were cultured. Primers were designed to amplify the exon-exon boundary predicted to be affected. Housekeeping gene expression was assessed to determine presence of RNA. Results: Total nucleic acid was successfully isolated for 10 variants from eight FFPE tumor tissues and two EBV-transformed B-cell lines. Aberrant splicing was confirmed in all six variants known to result in splicing. Of one known splice variant, present in the B-cell line, the known aberrant splice product could only be detected after formalin fixation of the cells, suggesting that formalin fixation possibly inhibited RNA degradation. Conclusion: Aberrant splicing was successfully identified in all known splice variants and three of four variants predicted to affect splicing, of which the splice effect was previously unknown. Using a RNA sequencing approach, somatic splice variants could be easily and rapidly analyzed, enabling retrospective analysis of variants predicted to result in splicing when only FFPE material is available in clinical settings. Citation Format: Anne M. Jansen, Heleen M. van der Klift, Jaap D. van Eendenburg, Carli M. Tops, Juul T. Wijnen, Frederik J. Hes, Ajay Goel, Hans Morreau, Tom van Wezel. Development of a novel RNA sequencing approach that identifies aberrant splicing in cancer predisposing genes [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 649.