tbuckley/cabot-search huggingface dataset:
Genetics is a major determinant of expression of the human hepatic uptake transporter OATP1B1, but not of OATP1B3 and OATP2B1
Authors: Anne T Nies, Mikko Niemi, Oliver Burk, Stefan Winter, Ulrich M Zanger, Bruno Stieger, Matthias Schwab, Elke Schaeffeler
Journal: Genome Medicine (2013)

Abstract Background Organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and OATP2B1 (encoded by SLCO1B1, SLCO1B3, SLCO2B1 ) mediate the hepatic uptake of endogenous compounds like bile acids and of drugs, for example, the lipid-lowering atorvastatin, thereby influencing hepatobiliary elimination. Here we systematically elucidated the contribution of SLCO variants on expression of the three hepatic OATPs under consideration of additional important covariates. Methods Expression was quantified by RT-PCR and immunoblotting in 143 Caucasian liver samples. A total of 109 rare and common variants in the SLCO1B3-SLCO1B1 genomic region and the SLCO2B1 gene were genotyped by MALDI-TOF mass spectrometry and genome-wide SNP microarray technology. SLCO1B1 haplotypes affecting hepatic OATP1B1 expression were associated with pharmacokinetic data of the OATP1B1 substrate atorvastatin ( n = 82). Results Expression of OATP1B1, OATP1B3, and OATP2B1 at the mRNA and protein levels showed marked interindividual variability. All three OATPs were expressed in a coordinated fashion. By a multivariate regression analysis adjusted for non-genetic and transcription covariates, increased OATP1B1 expression was associated with the coding SLCO1B1 variant c.388A &gt; G (rs2306283) even after correction for multiple testing ( P = 0.00034). This held true for haplotypes harboring c.388A &gt; G but not the functional variant c.521T &gt; C (rs4149056) associated with statin-related myopathy. c.388A &gt; G also significantly affected atorvastatin pharmacokinetics. SLCO variants and non-genetic and regulatory covariates together accounted for 59% of variability of OATP1B1 expression. Conclusions Our results show that expression of OATP1B1, but not of OATP1B3 and OATP2B1, is significantly affected by genetic variants. The SLCO1B1 variant c.388A &gt; G is the major determinant with additional consequences on atorvastatin plasma levels.
Awareness and Treatment of Dyslipidemia in Young Adults With Type 1 Diabetes
Authors: R. Paul Wadwa, Gregory L. Kinney, David M. Maahs, Janet Snell-Bergeon, John E. Hokanson, Satish K. Garg, Robert H. Eckel, Marian Rewers
Journal: Diabetes Care (2005)

OBJECTIVE—Dyslipidemia is a preventable major risk factor for coronary heart disease (CHD). Despite an increased risk of CHD in type 1 diabetes, little is known concerning awareness and adequacy of dyslipidemia treatment in this population. In this report, we describe the prevalence of dyslipidemia and adequacy of pharmacological treatment in patients with type 1 diabetes and comparable nondiabetic subjects. RESEARCH DESIGN AND METHODS—From 2000 to 2002, the Coronary Artery Calcification in Type 1 Diabetes study obtained fasting lipid profiles in 1,416 individuals aged 19–56 years with no history of CHD: 652 type 1 diabetic patients (46% men, mean age 37 ± 9 years) and 764 nondiabetic control subjects (50% men, mean age 39 ± 9 years). These data combined with patient questionnaire results were used to determine prevalence of dyslipidemia and adequacy of pharmacological treatment. For all subjects, dyslipidemia was defined using National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS—Type 1 diabetic subjects had significantly less dyslipidemia than nondiabetic control subjects (47 vs. 58%, P &amp;lt; 0.001), and a higher percentage of those with abnormal lipids were aware of (52 vs. 34%, P &amp;lt; 0.0001), on medication for (36 vs. 9%, P &amp;lt; 0.0001), and in control of their lipid levels (15 vs. 1.4%, P &amp;lt; 0.001). Of those on treatment, control was achieved in 41% of type 1 diabetic subjects and 15% of nondiabetic participants (P &amp;lt; 0.01). CONCLUSIONS—Dyslipidemia, a major risk factor for CHD, remains largely undiagnosed and undertreated in high-risk populations, such as patients with type 1 diabetes.
How Prostacyclin Improves Cardiac Output in Right Heart Failure in Conjunction with Pulmonary Hypertension
Authors: François Kerbaul, Serge Brimioulle, Benoı̂t Rondelet, Céline Dewachter, Ives Hubloue, Robert Naeije
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Rationale: Prostacyclin therapy improves patients with pulmonary arterial hypertension, but whether this is attributable to an improved inotropic state of the right ventricle in addition to a decreased pulmonary arterial pulmonary vascular resistance remains unclear.Objectives: We measured the effects of prostacyclin on load-independent measurements of right ventricular contractility in a model of load-induced acute right ventricular failure.Methods and Results: Persistent right ventricular failure was induced in dogs by a transient (90 min) pulmonary arterial constriction. After constriction release and stabilization, intravenous prostacyclin (epoprostenol) was given at doses of 6 and 12 ng/kg/minute for 30 minutes. Pulmonary vascular resistance was assessed by pressure–flow relationships and right ventricular afterload by effective pulmonary arterial elastance. Right ventricular contractility was estimated by end-systolic elastance and right ventriculoarterial coupling efficiency by the ratio of these elastances. Transient pulmonary arterial constriction persistently increased pulmonary vascular resistance, increased arterial elastance from 1.00 ± 0.07 to 2.86 ± 0.26 mm Hg/ml, decreased end-systolic elastance from 1.11 ± 0.07 to 0.54 ± 0.02 mm Hg/ml, decreased the ratio of elastances from 1.14 ± 0.08 to 0.20 ± 0.02, and cardiac output from 4.6 ± 0.1 to 2.3 ± 0.1 L/min (p < 0.05). Epoprostenol did not affect end-systolic elastance; however, it decreased arterial elastance to 1.84 ± 0.33 mm Hg/ml, and increased the ratio of elastances to 0.46 ± 0.17 and cardiac output to 3.4 ± 0.3 L/min (p < 0.05).Conclusions: In this model of afterload-induced right ventricular failure, prostacyclin improves right ventriculoarterial coupling and cardiac output because of vasodilating effects.
To ligate or sclerose: Beginning of a new era in the management of esophageal varices?
Authors: S. K. Sarin, V. Bhatia
Journal: Hepatology (1993)

Background. Endoscopic sclerotherapy is an accepted treatment for bleeding esophageal varices, but it is associated with substantial local and systemic complications. Endoscopic ligation, a new form of endoscopic treatment for bleeding varices, may be safer. We compared the effectiveness and safety of the two techniques. Methods. In this randomized trial we compared endoscopic sclerotherapy and endoscopic ligation in 129 patients with cirrhosis who had proved bleeding from esophageal varices. Sixty-five patients were treated with sclerotherapy, and 64 with ligation. Initial treatment for acute bleeding was followed by elective retreatment to eradicate varices. The patients were followed for a mean of 10 months, during which we determined the incidence of complications and recurrences of bleeding, the number of treatments needed to eradicate varices, and survival. Results. Active bleeding at the first treatment was controlled by sclerotherapy in 10 of 13 patients (77 percent) and by ligation in 12 of 14 patients (86 percent). Slightly more sclerotherapy-treated patients had recurrent hemorrhage during the study (48 percent vs. 36 percent for the ligation-treated patients, P = 0.072). The eradication of varices required a lower mean (± SD) number of treatments with ligation (4 ± 2 vs. 5 ± 2, P = 0.056) than with sclerotherapy. The mortality rate was significantly higher in the sclerotherapy group (45 percent vs. 28 percent, P = 0.041), as was the rate of complications (22 percent vs. 2 percent, P < 0.001). The complications of sclerotherapy were predominantly esophageal strictures, pneumonias, and other infections. Conclusions. Patients with cirrhosis who have bleeding esophageal varices have fewer treatment-related complications and better survival rates when they are treated by esophageal ligation than when they are treated by sclerotherapy. N Engl J Med 1992;326:1527–1532.
The challenge of West Nile virus in Europe: knowledge gaps and research priorities
Authors: A Rizzoli, M A Jiménez-Clavero, L Barzon, P Cordioli, J Figuerola, P Koraka, B Martina, A Moreno, N Nowotny, N Pardigon, N Sanders, S Ulbert, A Tenorio
Journal: Eurosurveillance (2015)

West Nile virus (WNV) is continuously spreading across Europe, and other continents, i.e. North and South America and many other regions of the world. Despite the overall sporadic nature of outbreaks with cases of West Nile neuroinvasive disease (WNND) in Europe, the spillover events have increased and the virus has been introduced into new areas. The high genetic diversity of the virus, with remarkable phenotypic variation, and its endemic circulation in several countries, require an intensification of the integrated and multidisciplinary research efforts built under the 7th Framework Programme of the European Union (FP7). It is important to better clarify several aspects of WNV circulation in Europe, including its ecology, genomic diversity, pathogenicity, transmissibility, diagnosis and control options, under different environmental and socio-economic scenarios. Identifying WNV endemic as well as infection-free areas is becoming a need for the development of human vaccines and therapeutics and the application of blood and organs safety regulations. This review, produced as a joint initiative among European experts and based on analysis of 118 scientific papers published between 2004 and 2014, provides the state of knowledge on WNV and highlights the existing knowledge and research gaps that need to be addressed with high priority in Europe and neighbouring countries.
Circulating Microparticles From Patients With Myocardial Infarction Cause Endothelial Dysfunction
Authors: Chantal M. Boulanger, Alexandra Scoazec, Talin Ebrahimian, Patrick Henry, Eric Mathieu, Alain Tedgui, Ziad Mallat
Journal: Circulation (2001)

Background Shed membrane microparticles circulate in the peripheral blood of nonischemic (NI) patients and patients with myocardial infarction (MI). We investigated whether or not these microparticles would affect endothelium-dependent responses. Methods and Results Rat aortic rings with endothelium were exposed for 24 hours to circulating microparticles isolated from 7 patients with NI syndromes and 19 patients with acute MI. Endothelium-dependent relaxations to acetylcholine were not affected by high concentrations of microparticles from NI patients ( P =0.80). However, significant impairment was observed in preparations exposed to microparticles from patients with MI at low and high concentrations, corresponding to 0.7-fold and 2-fold circulating plasma levels ( P =0.05 and 0.001, respectively). Impairment was not affected by diclofenac ( P =0.47), nor by the cell-permeable superoxide dismutase mimetic Mn(III)tetra(4-benzoic acid) porphyrin chloride ( P =0.33), but it was abolished by endothelium removal or by N ω monomethyl- l -arginine. Relaxations to the calcium ionophore ionomycin were decreased in rings exposed to microparticles from MI patients ( P =0.05 and 0.009 for low and high concentrations, respectively), but microparticles from NI patients had no effect ( P =0.81). Finally, high concentrations of microparticles from MI patients affected neither endothelium-independent relaxation to sodium nitroprusside ( P =0.59) nor expression of the endothelial nitric oxide synthase ( P =0.43). Conclusions Circulating microparticles from patients with MI selectively impair the endothelial nitric oxide transduction pathway and, therefore, could contribute to the general vasomotor dysfunction observed after MI, even in angiographically normal arteries.
Polyamine Regulation of N-Methyl-D-Aspartate Receptor Channels
Authors: D M Rock, R L Macdonald
Journal: The Annual Review of Pharmacology and Toxicology (1995)

Endogenous polyamines such as spermine and spermidine have multiple effects in the central nervous system and have been suggested to be neurotransmitters or neuromodulators. One effect of the polyamines is to regulate the activity of the N-methyl-D-aspartate receptor (NMDAR) channel subtype of glutamate receptor channels. The effects of polyamines on NMDAR currents are complex, suggesting the presence of one or more polyamine-binding sites on the receptor channel. Electrophysiological studies have shown that polyamines enhance NMDAR currents by increasing channel opening frequency and by increasing the affinity of the receptor for glycine. Polyamines have been shown to reduce NMDAR currents by producing voltage-dependent reduction of single-channel amplitudes and/or by producing an open channel block. Recent molecular biological studies have shown that the polyamine effects on NMDAR channels involve interactions with multiple NMDAR subunits and are characterizing the structural basis for the polyamine regulation of NMDAT receptor channels.
Phase I trial of dose-escalated cisplatin with concomitant cetuximab and hyperfractionated-accelerated radiotherapy in locally advanced squamous cell carcinoma of the head and neck
Authors: T. Kuhnt, A. Sandner, T. Wendt, R. Engenhart-Cabillic, G. Lammering, M. Flentje, G. Grabenbauer, A. Schreiber, A. Pirnasch, J. Dunst
Journal: Annals of Oncology (2010)
Contractile Behavior of the Left Ventricle in Diastolic Heart Failure
Authors: Gerard P. Aurigemma, Michael R. Zile, William H. Gaasch
Journal: Circulation (2006)

2][3] The mechanism underlying such failure has been thought to be principally diastolic because LV diastolic function is universally abnormal and systolic performance, function, and contractility are normal. 46][7][8][9] The significance of these findings, especially their relation to the syndrome of heart failure, remains uncertain.Accordingly, we will review some of the structural and functional differences between systolic and diastolic heart failure, and, emphasizing the systolic or contractile behavior of the left ventricle, we will attempt to reconcile what appear to be disparate conclusions about LV systolic function in patients with diastolic heart failure. Structural RemodelingThe hearts of patients with systolic heart failure differ dramatically from those of patients with diastolic heart failure in regard to both gross and microscopic anatomic features.As will be seen, these anatomic differences tend to parallel physiological and functional differences in systolic and diastolic heart failure 10,11 (Table 1).
IMPACT OF PULMONARY VEIN ISOLATION TO PAROXISMAL ATRIAL FIBRILLATION FOR ATRIAL ASYNCHRONY AND GLOBAL STRAIN ASSESSED BY 3D STRAIN ECHOCARDIOGRAPHY
Authors: Yukari Kobayashi, Keizo Yamamoto, Yuhei Kobayashi, Kimikazu Banba, Atsushi Hirohata, Tohru Ohe
Journal: Journal of the American College of Cardiology (2013)
Rap1b facilitates NK cell functions via IQGAP1-mediated signalosomes
Authors: Aradhana Awasthi, Asanga Samarakoon, Haiyan Chu, Rajasekaran Kamalakannan, Lawrence A. Quilliam, Magdalena Chrzanowska-Wodnicka, Gilbert C. White, Subramaniam Malarkannan
Journal: The Journal of Experimental Medicine (2010)

Rap1 GTPases control immune synapse formation and signaling in lymphocytes. However, the precise molecular mechanism by which Rap1 regulates natural killer (NK) cell activation is not known. Using Rap1a or Rap1b knockout mice, we identify Rap1b as the major isoform in NK cells. Its absence significantly impaired LFA1 polarization, spreading, and microtubule organizing center (MTOC) formation in NK cells. Neither Rap1 isoform was essential for NK cytotoxicity. However, absence of Rap1b impaired NKG2D, Ly49D, and NCR1-mediated cytokine and chemokine production. Upon activation, Rap1b colocalized with the scaffolding protein IQGAP1. This interaction facilitated sequential phosphorylation of B-Raf, C-Raf, and ERK1/2 and helped IQGAP1 to form a large signalosome in the perinuclear region. These results reveal a previously unrecognized role for Rap1b in NK cell signaling and effector functions.
PD-L1/B7H-1 Inhibits the Effector Phase of Tumor Rejection by T Cell Receptor (TCR) Transgenic CD8+ T Cells
Authors: Christian Blank, Ian Brown, Amy C. Peterson, Mike Spiotto, Yoshiko Iwai, Tasuku Honjo, Thomas F. Gajewski
Journal: Cancer Research (2004)

Abstract Although increased circulating tumor antigen-specific CD8+ T cells can be achieved by vaccination or adoptive transfer, tumor progression nonetheless often occurs through resistance to effector function. To develop a model for identifying mechanisms of resistance to antigen-specific CTLs, poorly immunogenic B16-F10 melanoma was transduced to express the Kb-binding peptide SIYRYYGL as a green fluorescent protein fusion protein that should be recognized by high-affinity 2C TCR transgenic T cells. Although B16.SIY cells expressed high levels of antigen and were induced to express Kb in response to IFN-γ, they were poorly recognized by primed 2C/RAG2−/− T cells. A screen for candidate inhibitory ligands revealed elevated PD-L1/B7H-1 on IFN-γ-treated B16-F10 cells and also on eight additional mouse tumors and seven human melanoma cell lines. Primed 2C/RAG2−/−/PD-1−/− T cells showed augmented cytokine production, proliferation, and cytolytic activity against tumor cells compared with wild-type 2C cells. This effect was reproduced with anti-PD-L1 antibody present during the effector phase but not during the priming culture. Adoptive transfer of 2C/RAG2−/−/PD-1−/− T cells in vivo caused tumor rejection under conditions in which wild-type 2C cells or CTLA-4-deficient 2C cells did not reject. Our results support interfering with PD-L1/PD-1 interactions to augment the effector function of tumor antigen-specific CD8+ T cells in the tumor microenvironment.
PENETRATION AND DOSE OF INJECTIONS WITH THE PORTON JET INJECTOR
Authors: P. GAYLARDE, A. L. MACMILLAN, I. SARKANY
Journal: British Journal of Dermatology (1972)

Journal Article PENETRATION AND DOSE OF INJECTIONS WITH THE PORTON JET INJECTOR Get access P. GAYLARDE, P. GAYLARDE Department of Dermatology, The Royal Free, Hospital, London, W.C.I Search for other works by this author on: Oxford Academic Google Scholar A. L. MACMILLAN, A. L. MACMILLAN Department of Dermatology, The Royal Free, Hospital, London, W.C.I Search for other works by this author on: Oxford Academic Google Scholar I. SARKANY I. SARKANY Department of Dermatology, The Royal Free, Hospital, London, W.C.I Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 86, Issue 1, 1 January 1972, Pages 83–86, https://doi.org/10.1111/j.1365-2133.1972.tb01898.x Published: 01 January 1972 Article history Accepted: 07 September 1971 Published: 01 January 1972
Hypercoagulability Inhibits Monocyte Transendothelial Migration Through Protease-Activated Receptor-1-, Phospholipase-Cβ-, Phosphoinositide 3-Kinase-, and Nitric Oxide-Dependent Signaling in Monocytes and Promotes Plaque Stability
Authors: Stefanie Seehaus, Khurrum Shahzad, Muhammed Kashif, Ilya A. Vinnikov, Martin Schiller, Hongjie Wang, Thati Madhusudhan, Volker Eckstein, Angelika Bierhaus, Florian Bea, Erwin Blessing, Hartmut Weiler, David Frommhold, Peter P. Nawroth, Berend Isermann
Journal: Circulation (2009)

Clinical studies failed to provide clear evidence for a proatherogenic role of hypercoagulability. This is in contrast to the well-established detrimental role of hypercoagulability and thrombin during acute atherosclerotic complications. These seemingly opposing data suggest that hypercoagulability might exert both proatherogenic and antiatherogenic effects. We therefore investigated whether hypercoagulability mediates a beneficial effect during de novo atherogenesis.De novo atherogenesis was evaluated in 2 mouse models with hyperlipidemia and genetically imposed hypercoagulability (TM(Pro/Pro)ApoE(-/-) and FVL(Q/Q)ApoE(-/-) mice). In both mouse models, hypercoagulability resulted in larger plaques, but vascular stenosis was not enhanced secondary to positive vascular remodeling. Importantly, plaque stability was increased in hypercoagulable mice with less necrotic cores, more extracellular matrix, more smooth muscle cells, and fewer macrophages. Long-term anticoagulation reversed these changes. The reduced frequency of intraplaque macrophages in hypercoagulable mice is explained by an inhibitory role of thrombin and protease-activated receptor-1 on monocyte transendothelial migration in vitro. This is dependent on phospholipase-Cbeta, phosphoinositide 3-kinase, and nitric oxide signaling in monocytes but not in endothelial cells.Here, we show a new function of the coagulation system, averting stenosis and plaque destabilization during de novo atherogenesis. The in vivo and in vitro data establish that thrombin-induced signaling via protease-activated receptor-1, phospholipase-Cbeta, phosphoinositide 3-kinase, and nitric oxide in monocytes impairs monocyte transendothelial migration. This likely accounts for the reduced macrophage accumulation in plaques of hypercoagulable mice. Thus, in contrast to their role in unstable plaques or after vascular injury, hypercoagulability and thrombin convey a protective effect during de novo atherogenesis.
A novel disease-modifying osteoarthritis drug candidate targeting Runx1
Authors: Fumiko Yano, Hironori Hojo, Shinsuke Ohba, Atsushi Fukai, Yoko Hosaka, Toshiyuki Ikeda, Taku Saito, Makoto Hirata, Hirotaka Chikuda, Tsuyoshi Takato, Hiroshi Kawaguchi, Ung-il Chung
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> To identify a new disease-modifying osteoarthritis drug (DMOAD) candidate that can effectively repair cartilage by promoting chondrogenic differentiation and halt osteoarthritis (OA) progression by suppressing aberrant hypertrophy. <h3>Methods</h3> We screened 2500 natural and synthetic small compounds for chondrogenic agents via four steps using the Col2GFP-ATDC5 system and identified a small thienoindazole derivative compound, TD-198946, as a novel DMOAD candidate. We tested its efficacy as a DMOAD via intra-articular injections directly into the joint space in a surgically-induced mouse model of OA both at the onset (prevention model) and 4 weeks after (repair model) OA induction. The downstream molecules were screened by microarray analysis. We further investigated the mechanism of the drug action and its molecular target using in vitro and in vivo assays. <h3>Results</h3> TD-198946 strongly induced chondrogenic differentiation without promoting hypertrophy in cell and metatarsal organ cultures. When administered directly into the joint space, TD-198946 successfully prevented and repaired degeneration of the articular cartilage. TD-198946 exerted its effect through the regulation of Runx1 expression, which was downregulated in both mouse and human OA cartilage compared with normal tissue. <h3>Conclusions</h3> Our data suggest that TD-198946 is a novel class of DMOAD candidate, and that targeting Runx1 will provide a promising new approach in the development of disease-modifying drugs against OA.
Micelles and Microemulsions in Ionic Surfactant and Bile Salt Systems Studied by Self-Diffusion
Authors: BjÖRn Lindman
Journal: Hepatology (1984)

Multicomponent self-diffusion studies provide a general picture of amphiphile self-association. Both micelles and microemulsions based on bile salts show a lower degree of association cooperativity, lower aggregate charge densities and more extensive hydration than corresponding ionic surfactant systems. Effectively bicontinuous isotropic solutions of the microemulsion type are more easily formed by bile salts than by surfactants.