tbuckley/cabot-search huggingface dataset:
Impact of Plasma Oxidized Low-Density Lipoprotein Removal on Atherosclerosis
Authors: YasushiIshigaki, HidekiKatagiri, JunhongGao, TetsuyaYamada, JuntaImai, KenjiUno, YutakaHasegawa, KeizoKaneko, TakehideOgihara, HisamitsuIshihara, YukoSato, KenjiTakikawa, NorihisaNishimichi, HaruoMatsuda, TatsuyaSawamura, YoshitomoOka
Journal: Circulation (2008)

Background— Several clinical studies of statin therapy have demonstrated that lowering low-density lipoprotein (LDL) cholesterol prevents atherosclerotic progression and decreases cardiovascular mortality. In addition, oxidized LDL (oxLDL) is suggested to play roles in the formation and progression of atherosclerosis. However, whether lowering oxLDL alone, rather than total LDL, affects atherogenesis remains unclear. Methods and Results— To clarify the atherogenic impact of oxLDL, lectin-like oxLDL receptor 1 (LOX-1), an oxLDL receptor, was expressed ectopically in the liver with adenovirus administration in apolipoprotein E–deficient mice at 46 weeks of age. Hepatic LOX-1 expression enhanced hepatic oxLDL uptake, indicating functional expression of LOX-1 in the liver. Although plasma total cholesterol, triglyceride, and LDL cholesterol levels were unaffected, plasma oxLDL was markedly and transiently decreased in LOX-1 mice. In controls, atherosclerotic lesions, detected by Oil Red O staining, were marke...
Response to: ‘Digital health: a new dimension in rheumatology patient care’ by Kataria and Ravindran
Authors: Gerd R Burmester
Journal: Annals of the Rheumatic Diseases (2018)

directed to a recent article of mine in the new Annals of the Rheumatic Diseases section 'Thinking the unthinkable'. 2Their comments are much appreciated, especially since they re-emphasise the upcoming disruption in chronic diseases, but also outline the complexity that many tools will not yet be approved by regulatory authorities for use in daily routine care.Digital biomarkers will be important for the prediction of clinical outcomes, and they rightly point out that patterns arising from genome-wide association studies could be helpful in providing insights into disease pathology.They also allude to the important item of data protection, which has become even more important in Europe with the introduction of the New European General Data Protection Regulation, 3 which strongly enforces patients' rights.Finally, they rightly emphasise the role of the human being in artificial intelligence algorithms to validate the findings of these novel approaches.In the future, we will have to leave the sometimes comfortable cocoon to step into the digital world-of course aiming for a better and more rapid patient care.
Pharmacological Evidence for the Persistent Activation of ATP-Sensitive K+ Channels in Early Phase of Reperfusion and Its Protective Role Against Myocardial Stunning
Authors: SakujiShigematsu, ToshiakiSato, TakakoAbe, TetsunoriSaikawa, ToshiieSakata, MakotoArita
Journal: Circulation (1995)

Background The activation of cardiac ATP-sensitive potassium channels is reported to protect myocardium during ischemia. However, the behavior and role of this channel during reperfusion remain uncertain. Methods and Results Guinea pig right ventricular walls were studied by use of microelectrodes and a force transducer. Each preparation was perfused via the coronary artery at a constant flow rate and was stimulated at 3 Hz. In the first protocol, the preparation was subjected to 10 minutes of no-flow ischemia, which was followed by 60 minutes of reperfusion. Introduction of ischemia shortened the action potential duration (APD) to 58.7±3.1% of the preischemic values, in association with a decrease in the resting membrane potential (by 12±0.8 mV) and action potential amplitude (by 34.6±1.8 mV). On reperfusion, although the APD was restored, it remained shortened for up to approximately 30 minutes of reperfusion. In the presence of glibenclamide (10 μmol/L), the shortening of the APD during ischemia was si...
Abstract 2285: Regtools: Integrated analysis of genomic and transcriptomic data for discovery of mutations associated with aberrant splicing in cancer
Authors: Yang-Yang Feng, Avinash Ramu, Zachary L. Skidmore, Jason Kunisaki, Kelsy C. Cotto, Obi L. Griffith, Malachi Griffith
Journal: Cancer Research (2018)

Abstract The interpretation of variants in cancer is frequently focused on direct protein coding alterations. However, most somatic mutations are in noncoding regions of the genome, and even exonic mutations may have unidentified noncoding consequences. Here we present Regtools, a software package designed to efficiently identify variants that may cause aberrant splicing in tumors. Our tool integrates variant calls from genomic data with junctions extracted from transcriptomic data in order to examine potential cis alterations to splicing near a somatic variant. Based on user-defined parameters and position relative to known exons, variants are first annotated as splicing relevant or not. Splicing junctions are inferred from transcriptomic sequencing data, and comparison of junctions to a reference transcriptome allows for identification and annotation of novel junctions and nearby regulatory or splicing motifs. From there, mutations are associated with junctions that overlap with a flanking region. In order to evaluate Regtools, we used it to analyze the transcriptional output of tumor-sequencing data from two cohorts of cancer patients, one of hepatocellular carcinoma and one of small cell lung cancer with 28 and 21 samples, respectively. We performed whole-exome and RNA sequencing on each sample. Somatic variants were called on whole-exome alignment data. For each cohort, we compared the junctional profiles between tumors and identified numerous examples of variants for which there are elevated levels of proximal novel or known junctions. Moreover, out of 754 (153 in HCC; 601 in SCLC) variants identified as splicing relevant by our approach, only 165 (20 in HCC; 145 in SCLC) were annotated as splicing relevant by Ensembl's Variant Effect Predictor, using the recommended “per_gene” option. This preliminary analysis illustrates the importance of an efficient, user-friendly computational tool for identifying important noncoding variants that would otherwise be undervalued or perhaps even completely ignored by traditional methods and annotators. Regtools is freely available and open source (https://github.com/griffithlab/regtools). Citation Format: Yang-Yang Feng, Avinash Ramu, Zachary L. Skidmore, Jason Kunisaki, Kelsy C. Cotto, Obi L. Griffith, Malachi Griffith. Regtools: Integrated analysis of genomic and transcriptomic data for discovery of mutations associated with aberrant splicing in 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 2285.
Direct Measurements of Endothelium-Derived Nitric Oxide Release by Stimulation of Endothelin Receptors in Rat Kidney and Its Alteration in Salt-Induced Hypertension
Authors: YasunobuHirata, HiroshiHayakawa, EtsuSuzuki, KenjiroKimura, KazuyaKikuchi, TetsuoNagano, MasaakiHirobe, MasaoOmata
Journal: Circulation (1995)

Background Stimulation of endothelin subtype B (ETB) receptors has been proposed to induce release of endothelium-derived nitric oxide (EDNO). Methods and Results To obtain direct evidence of its release and its alteration in deoxycorticosterone acetate (DOCA)-salt hypertension, EDNO released from renal vessels by ET stimulation was assayed by a highly sensitive chemiluminescence method. Kidneys were isolated from DOCA-salt and control rats, and renal perfusion pressure (RPP) and EDNO (by hydrogen peroxide–luminol chemiluminescence) in the perfusate were monitored simultaneously during perfusion of ET-1, ET-3, an ETA receptor antagonist (BQ-123), and an ETB receptor agonist (BQ-3020). In control rats, ET-1 and ET-3 dose-dependently increased both RPP and NO release. Although the vasoconstricting effects of ET-1 were greater, their NO-releasing effects were comparable. The increase in NO release by ETs was inhibited by NG-monomethyl-l-arginine. After 10−6 mol/L BQ-123 treatment, ET-1 decreased RPP and incr...
Abstract 207: CML as a prototypical malignancy
Authors: Dmitriy Sonkin, Richard Simon
Journal: Cancer Research (2018)

Abstract Chronic myelogenous leukemia (CML) was the first malignancy for which clinical outcome was drastically improved by kinase inhibitor therapy. Kinase inhibitors targeting other well-known oncogenes have been introduced into clinical practice, but none have shown the same magnitude of clinical benefit as ABL1 inhibition in CML. CML is sometimes described as an atypical malignancy or a one-hit malignancy. However careful examination of accumulation of additional oncogenic alterations in genes such as TP53, CDKN2A/B, IKZF1 and RUNX1 during CML progression from chronic phase to blast phase indicates that this is not the case. Instead CML provides a window into how many types of cancer may look and behave at an early stage, prior to diagnosis and the development of additional genomic alterations. The remarkable clinical benefits of ABL1 inhibition is likely due to early detection of CML at a stage in which the tumor is driven by single oncogenic alteration which can be successfully controlled by the inhibitor. The majority of CML patients in chronic phase of the disease treated with ABL1 inhibitor achieve a major molecular response (MMR) which corresponds to 1000 times decrease in BCR-ABL fusion levels. As a result, there is drastic reduction in number of cells which may accumulate additional alterations in genes like TP53, CDKN2A/B, IKZF1, RUNX1 leading to greatly decreased chance of progression to blast crisis. Thinking of CML as a prototype for effective systemic treatment based on early cancer detection may help to provide strategies for improving treatment for other types of cancer. Citation Format: Dmitriy Sonkin, Richard Simon. CML as a prototypical malignancy [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 207.
Effect of Etilefrine in Preventing Syncopal Recurrence in Patients With Vasovagal Syncope
Authors: AntonioRaviele, MicheleBrignole, RichardSutton, PaoloAlboni, PaoloGiani, CarloMenozzi, AngelMoya
Journal: Circulation (1999)

Background—Etilefrine is an α-agonist agent with a potent vasoconstrictor effect, which is potentially useful in preventing vasovagal syncope by reducing venous pooling and/or by counteracting reflex arteriolar vasodilatation. The present multicenter, randomized, placebo-controlled study was designed to evaluate the efficacy of this drug for the long-term management of patients with recurrent vasovagal syncope. Methods and Results—In the 20 participating centers, 126 patients with recurrent vasovagal syncope (at least 3 episodes in the last 2 years) and a positive baseline head-up tilt response were randomly assigned to placebo (63 patients) or etilefrine at a dosage of 75 mg/d (63 patients) and were followed up for 1 year or until syncope recurred. The primary end-point of the study was the first recurrence of syncope. There were no differences between the 2 study groups in the patients’ baseline characteristics. During follow-up, the group treated with etilefrine had a similar incidence of first syncopa...
Endogenous Basic Fibroblast Growth Factor Displaced by Heparin From the Lumenal Surface of Human Blood Vessels Is Preferentially Sequestered by Injured Regions of the Vessel Wall
Authors: BenjaminMedalion, GideonMerin, HelenaAingorn, Hua-QuanMiao, ArnonNagler, AmirElami, RivkaIshai-Michaeli, IsraelVlodavsky
Journal: Circulation (1997)

Background Proliferation of smooth muscle cells (SMCs) of the arterial wall in response to local injury is an important factor in vascular proliferative disorders. Among the growth factors that promote SMC proliferation is basic fibroblast growth factor (bFGF), which is characterized by a high affinity for heparin and is associated with heparan sulfate on cell surfaces and extracellular matrices. We investigated whether heparin can displace endogenous active bFGF from the lumenal surface of blood vessels, whether bFGF is preferentially bound to injured blood vessels, and whether a synthetic, polyanionic, heparin-mimicking compound (RG-13577) can prevent sequestration of bFGF by the vessel wall. Methods and Results Injured and noninjured saphenous vein segments were perfused with or without heparin, in the absence or presence of 125I-bFGF and/or RG-13577 (a polymer of 4-hydroxyphenoxy acetic acid). Heparin displaced bFGF from the lumenal surface of the vein, and the released bFGF stimulated proliferation o...
Abstract 15415: Increase Arterial Stiffness in Patients with Later-Onset Cardiac Variant Fabry Disease
Authors: Hsin-Ru Li
Journal: Circulation (2012)

Background: The novel intron mutation ( IVS4+919G→A) has been reported to be associated with later-onset cardiac variant Fabry disease (FD) which could lead to left ventricular hypertrophy without other organ involvement. Aim of this study is to investigate the vascular properties between control and cardiac variant FD. Method: 39 controls and 23 cardiac variant FD patients without difference in age and renal function underwent echocardiography for left ventricular mass index (LVMI) and vascular function evaluation including carotid-femoral pulse wave velocity(cfPWV), carotid augmentation pressure(AP), carotid augmentation index(AIx), and carotid intima-media thickness(IMT). Result: The LVMI of cardiac variant FD are significant higher than control (116.13±46 vs. 81.98±18 g/m P=0.002 ). The AP and IMT, cfPWV are significantly higher in cardiac variant FD patients than in control(10.06±6.4 vs. 6.66± 6.2 mmHg P=0.047, 0.62±0.13 vs. 0.53± 0.13 cm P=0.015, 7.89±2 vs. 9.78±3.2 m/s P=0.006,). Conclusion: There ...
Bradykinin Mediation of Ca2+-Activated K+ Channels Regulates Coronary Blood Flow in Ischemic Myocardium
Authors: KoichiNode, MasafumiKitakaze, HiroakiKosaka, TetsuoMinamino, MasatsuguHori
Journal: Circulation (1997)

Background Endothelium-dependent hyperpolarizing factor relaxes vascular smooth muscles by opening the Ca2+-activated K+ (KCa) channels. The role of the opening of KCa channels in coronary vasodilation during myocardial ischemia was investigated. Methods and Results The left anterior descending coronary arteries of open-chest dogs were perfused with blood through an extracorporeal bypass tube from the carotid artery. Intracoronary administration of bradykinin increased coronary blood flow (CBF) in dogs treated with NG-nitro-l-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase; this effect was completely inhibited by the KCa channel blocker iberiotoxin. In dogs treated with L-NAME, the bypass tube was occluded to reduce CBF to one third of the baseline value, after which coronary perfusion pressure was maintained constant. Intracoronary administration of iberiotoxin for 20 minutes further decreased CBF (from 33±2 to 19±2 mL·100 g−1·min−1, P<.01), fractional shortening, and lactate extrac...
Abstract 2419: Lipid droplets promote glioblastoma cell growth through maintaining cholesterol homeostasis mediated by autophagy
Authors: Feng Geng, Xiang Cheng, Chunming Cheng, Arnab Chakravarti, Deliang Guo
Journal: Cancer Research (2018)

Abstract Lipid droplets (LDs) have been studied as the major storage site of neutral lipids for decades, especially in the progression of metabolic diseases. Recently, the functions of LDs in cancers have begun to gain significant attention. Here, we provide evidence that LDs promote glioblastoma (GBM) cell growth through autophagy mediated maintenance of cholesterol homeostasis. Our data showed that LDs in tumor tissues from GBM patients are engulfed by autophagic vacuoles and lysosomes. Cellular cholesterol deprivation or removal of plasma membrane cholesterol by methyl-β-cyclodextrin (MβCD) activates autophagy to hydrolyze LDs to support GBM cell survival, whereas inhibition of autophagy blocks transportation of cholesterol to plasma membrane, leading to cell death. Fluorescence imaging reveals direct trafficking of LD-stored cholesterol to the plasma membrane through autophagic liberation. Our data demonstrate that LDs serve as cholesterol reservoir for GBM cell growth, suggesting that targeting LD-autophagy-cholesterol homeostasis metabolic pathway represents a potential means to treat GBM and other malignancies. Citation Format: Feng Geng, Xiang Cheng, Chunming Cheng, Arnab Chakravarti, Deliang Guo. Lipid droplets promote glioblastoma cell growth through maintaining cholesterol homeostasis mediated by autophagy [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 2419.
Abstract 622: Differential impact of pembrolizumab and ipilimumab on IFNgamma and IL-10 production from <i>in-vitro</i> monocyte-derived DC and T cell co-cultures
Authors: Tina Tang, Fay Stewart, Alexander Roberts, John Gordon, John Curnow, Nicholas Barnes, Omar Qureshi
Journal: Cancer Research (2018)

Abstract Despite the success with checkpoint inhibitors in-vivo, demonstrating efficacy in-vitro using human primary immune cells remains a challenge. Our aim was to determine the impact of pembrolizumab and ipilimumab on proliferation, as well as IFNγ and IL-10 production, from monocyte-derived dendritic cell and T cell co-cultures. CD14+ monocytes from the peripheral blood of healthy donors were isolated before differentiating into immature dendritic cells (iDC) with IL-4 and GM-CSF. Immature dendritic cells were subsequently matured (mDC) by exposure to IL-1β, IL-6, TNFα and PGE2. Allogeneic purified CD4+ T cells (from healthy donors) were co-cultured with either iDC or mDC in the absence (media alone or isotype control) or presence of either pembrolizumab or ipilimumab. T cell proliferation and IFNγ and IL-10 secretion were subsequently assessed. Whilst there was no consistent impact of either pembrolizumab or ipilimumab on the proliferation of CD4+ T cells in co-culture with iDC or mDC, IFNγ secretion by CD4+ T cells was increased in iDC- and mDC-co-cultures by pembrolizumab (percentage increase at 1μg/ml compare to isotype control: 524.5±196.1, P=0.037; 200.7±80.6, P=0.047, respectively, n=7) and reduced in iDC cultures with ipilimumab (percentage increase at 1μg/ml compared to isotype control: -63.4±11.7, P=0.012, n=4). IL-10 secretion was also impacted upon by pembrolizumab, whereby it increased in both iDC and mDC cultures with CD4+ T cells (percentage increase at 1μg/ml compare to isotype control: 175.3±27.0, P=0.003; 183.2±16.7, P&amp;lt;0.001, respectively, n=4). Ipilimumab however, whilst having no evident effect in iDC-T cell co-cultures, reduced IL-10 production of mDC co-cultures (percentage decrease at 1μg/ml compare to isotype control: -27.7±6.3, P=0.022, n=4). These data support the positive in-vivo results with pembrolizumab and ipilimumab, and demonstrates a reliable method for investigating the impact of checkpoint inhibitors in immune cells. Citation Format: Tina Tang, Fay Stewart, Alexander Roberts, John Gordon, John Curnow, Nicholas Barnes, Omar Qureshi. Differential impact of pembrolizumab and ipilimumab on IFNgamma and IL-10 production from in-vitro monocyte-derived DC and T cell co-cultures [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 622.
Abstract 1965: Biologic evaluation of chalcone derivatives as ABCG2- and ABCB1-mediated drug resistance reversal agents
Authors: Chaoyun Cai
Journal: Cancer Research (2018)

Abstract The overexpression of ATP-binding (ABC) transporters, including ABCG2 and ABCB1, has been shown to be related to multidrug resistance (MDR). In this work, we investigated a series of chalcones and bis-chalcones as ABCG2- and ABCB1-mediated resistance reversal agents. The results revealed that methoxyl chalcones have better reversal activities than hydroxyl chalcones toward ABCG2-mediated resistance. One methoxyl chalcone has good reversal activities in both ABCG2 and ABCB1 overexpressing cell lines. The compound can increase the accumulation of anticancer drugs in ABCG2 or ABCB1 overexpressing cell lines while combined with anticancer drugs, due to its inhibition of ABCG2 and ABCB1 (IC50 (ABCB1) =1.54 μM, IC50 (ABCG2) = 1.15 μM). In addition, this compound did not significantly alter the expression and localization of ABCG2 or ABCB1 in ABCG2 or ABCB1 overexpressing cell lines. Citation Format: Chaoyun Cai. Biologic evaluation of chalcone derivatives as ABCG2- and ABCB1-mediated drug resistance reversal agents [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 1965.
Abstract MP73: Geographic Variation of Overweight and Obesity among Women in Sub-Saharan Africa: a Case Study of Nigeria
Authors: SaverioStranges, Ngianga-BakwinKandala
Journal: Circulation (2014)

Background: Nutritional research in sub-Saharan Africa has primarily focused on under-nutrition, particularly among vulnerable population subgroups such as women and children. However, there is growing evidence of an ongoing epidemiological and nutritional transition in these settings. Objective: This study aimed to examine the geographic variation of combined overweight and obesity prevalence at the state-level among women in Nigeria, while accounting for individual-level risk factors. Methods: Our analysis was based on the 2008 Nigerian Demographic and Health Survey (NDHS), including 27,967 women aged 15 and over. Individual data were collected on socio-demographic variables, but were aggregated to the 31 states. We used a Bayesian geo-additive mixed model to map the geographic distribution of overweight/obesity at the state-level, accounting for individual-level risk factors. Results: The overall prevalence of combined overweight and obesity (body mass index ≥ 25) was 20.9%. In multivariate Bayesian ge...
Abstract 12737: Physiological Balance Between Nitric Oxide and Endothelium-Derived Hyperpolarizing Factor Plays a Crucial Role in Cardiovascular Homeostasis
Authors: ShigeoGodo, HirokiSaito, AyukoSawada, SaoriSato, ShuheiTanaka, HiroakiShimokawa
Journal: Circulation (2014)

Background: The endothelium modulates vascular tone by synthesizing and releasing endothelium-derived relaxing factors (EDRFs), including prostacyclin, nitric oxide (NO) and endothelium-derived hyperpolarizing factors (EDHFs). The contribution of each EDRF to endothelium-dependent vasodilatation varies depending on the vessel size; conduit arteries are primarily regulated by NO and resistance arteries by EDHFs, regardless of species and blood vessels tested. We have recently demonstrated that caveolin-1 (Cav-1), which functionally inhibits the activity of endothelial NO synthase (eNOS), is substantially involved in the functional inhibition of eNOS in resistance vessels in mice. However, the significance of the physiological balance between NO and EDHF in cardiovascular homeostasis remains to be elucidated. Methods and Results: We used 3 genotypes of mice including wild-type (WT), Cav-1-knockout (Cav-1-KO) and endothelium-specific eNOS transgenic (eNOS-Tg) mice; in the latter 2 genotypes eNOS activity is ...
Surgical airway education – Are junior trainees prepared for “Can’t intubate, Can’t ventilate?”
Authors: O. Sheikh, G. Logan, P. Zaringhalam, S. Basyuni, H. Mohammedbhai, S. Vempaty, R. Chandegra, M. Azizi, C.-B. Man, L. Ioannidi, M. Shorafa
Journal: International Journal of Surgery (2018)