tbuckley/cabot-search huggingface dataset:
New Efficient Catheter-Based System for Myocardial Gene Delivery
Authors: Ronen Beeri, J. Luis Guerrero, Gregory Supple, Suzanne Sullivan, Robert A. Levine, Roger J. Hajjar
Journal: Circulation (2002)

Manipulating gene expression in the failing heart has therapeutic promise, but until now efficient and homogeneous cardiac gene delivery has required an open-chest approach. This study examines the hypothesis that vector delivery promoted by echo contrast microbubbles will be maximized by injection of the vectors into the aortic root with brief balloon occlusion above the sinuses, while at the same time prolonging diastole and vasodilating with acetylcholine (ACh) to maximize coronary exposure.After incubation with albumin-coated perfluorocarbon microbubbles, an adenovirus encoding a reporter gene was infused into the aortic root of rats. To maximize delivery, the aortic root was transiently occluded with a balloon catheter during a brief ACh-induced asystole. Ultrasound was used to image the delivery and disrupt the microbubbles. Aortic occlusion with concomitant ACh increased myocardial gene expression for virus + microbubbles by >2.5-fold, from 925+/-165 to 2358+/-376 relative units (RU; P<0.01). This delivery system also produced substantial expression with vector alone (1473+/-549 RU). All uptakes were significant compared with 433+/-332 RU without virus.An adenoviral delivery system combining echo contrast with a catheter-based technique to maximize coronary perfusion increases gene delivery compared with echo contrast alone. This novel method permits efficient percutaneous gene delivery in closed-chest animals.
Integrin Targeted MR Imaging
Authors: Mingqian Tan, Zheng-Rong Lu
Journal: Theranostics (2011)

Magnetic resonance imaging (MRI) is a powerful medical diagnostic imaging modality for integrin targeted imaging, which uses the magnetic resonance of tissue water protons to display tissue anatomic structures with high spatial resolution.Contrast agents are often used in MRI to highlight specific regions of the body and make them easier to visualize.There are four main classes of MRI contrast agents based on their different contrast mechanisms, including T 1 , T 2 , chemical exchange saturation transfer (CEST) agents, and heteronuclear contrast agents.Integrins are an important family of heterodimeric transmembrane glycoproteins that function as mediators of cell-cell and cell-extracellular matrix interactions.The overexpressed integrins can be used as the molecular targets for designing suitable integrin targeted contrast agents for MR molecular imaging.Integrin targeted contrast agent includes a targeting agent specific to a target integrin, a paramagnetic agent and a linker connecting the targeting agent with the paramagnetic agent.Proper selection of targeting agents is critical for targeted MRI contrast agents to effectively bind to integrins for in vivo imaging.An ideal integrin targeted MR contrast agent should be non-toxic, provide strong contrast enhancement at the target sites and can be completely excreted from the body after MR imaging.An overview of integrin targeted MR contrast agents based on small molecular and macromolecular Gd(III) complexes, lipid nanoparticles and superparamagnetic nanoparticles is provided for MR molecular imaging.By using proper delivery systems for loading sufficient Gd(III) chelates or superparamagnetic nanoparticles, effective molecular imaging of integrins with MRI has been demonstrated in animal models.
Delayed-type hypersensitivity to low molecular weight heparins and heparinoids: cross-reactivity does not depend on molecular weight. Commentary
Authors: A. Gómez-Outes, C. Gómez de la Bárcena, J. Martínez-González
Journal: British Journal of Dermatology (2008)

Journal Article Delayed‐type hypersensitivity to low molecular weight heparins and heparinoids: cross‐reactivity does not depend on molecular weight. Commentary Get access A. Gómez‐Outes, A. Gómez‐Outes Medical Department, Laboratorios Farmacéuticos Rovi S.A., C/ Julián Camarillo, 35, 28037 Madrid, Spain E‐mail: agomez@rovi.es Search for other works by this author on: Oxford Academic Google Scholar C. Gómez de la Bárcena, C. Gómez de la Bárcena Medical Department, Laboratorios Farmacéuticos Rovi S.A., C/ Julián Camarillo, 35, 28037 Madrid, Spain E‐mail: agomez@rovi.es Search for other works by this author on: Oxford Academic Google Scholar J. Martínez‐González J. Martínez‐González Medical Department, Laboratorios Farmacéuticos Rovi S.A., C/ Julián Camarillo, 35, 28037 Madrid, Spain E‐mail: agomez@rovi.es Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 158, Issue 4, 1 April 2008, Pages 869–870, https://doi.org/10.1111/j.1365-2133.2008.08453.x Published: 01 April 2008
The contractile state as the major determinant in the evolution of left ventricular dysfunction in the spontaneously hypertensive rat.
Authors: I Mirsky, J M Pfeffer, M A Pfeffer, E Braunwald
Journal: Circulation Research (1983)

Female spontaneously hypertensive and normotensive rats were studied at 6, 12, 18, and 24 months of age to determine which characteristics of myocardial performance herald the onset of left ventricular dysfunction. Peak ejection fraction index was derived from measurements of peak stroke volume (in vivo volume loading) and passive pressure-volume relations. The myocardial stiffness constant (km, slope of the incremental modulus-stress relation, EINC = km sigma), chamber stiffness constant (kc, slope of the chamber stiffness-pressure relation, dP/dV = kcP), and left ventricular cavitary volume-to-wall volume ratio at 10 mm Hg) were calculated from the pressure-volume data and the contractile state was assessed from the ejection fraction index-afterload relations. In the normotensive rats, the myocardial stiffness constant was not affected by age, whereas, in the spontaneously hypertensive rats, the myocardial stiffness constant remained within normal limits until 18 months, at which time a significant increase in this index of myocardial stiffness occurred. Baseline and maximal cardiac indices and ejection fraction index of spontaneously hypertensive rats were normal from 6 to 18 months, but were markedly reduced at 24 months. This reduction in cardiac performance was associated with a decrease in the left ventricular chamber stiffness constant, i.e., kc. This decreased chamber stiffness, which occurred at a time when myocardial stiffness was increased, was due to a greater increase in cavity size than in myocardial stiffness. The left ventricular cavity-to-wall volume ratio of normotensive rats was not affected by age, whereas, in the spontaneously hypertensive rats, this ratio markedly declined by 18 months. The ejection fraction index-afterload relations i.e., a measure of the contractile state, of the 6- and 12-month-old spontaneously hypertensive rats were similar to those of the normotensive rats of all ages. However, a depression in the contractile state of the spontaneously hypertensive rats occurred at 18 months and was further depressed at 24 months. This abnormality of the contractile state was evident before the deterioration of cardiac performance, as reflected in a decrease in baseline and maximal cardiac indices, and dilation of the left ventricle occurred. The contractile state (ejection fraction index-afterload relation) is thus the most sensitive indicator of left ventricular dysfunction in spontaneously hypertensive rats.
Organization of heart failure management in European Society of Cardiology member countries: survey of the Heart Failure Association of the European Society of Cardiology in collaboration with the Heart Failure National Societies/Working Groups
Authors: Petar M. Seferović, Stefan Stoerk, Gerasimos Filippatos, Viacheslav Mareev, Ausra Kavoliuniene, Arsen D. Ristić, Piotr Ponikowski, John McMurray, Aldo Maggioni, Frank Ruschitzka, Dirk J. van Veldhuisen, Andrew Coats, Massimo Piepoli, Theresa McDonagh, Jillian Riley, Arno Hoes, Burkert Pieske, Milan Dobrić, Zoltan Papp, Alexandre Mebazaa, John Parissis, Tuvia Ben Gal, Dragos Vinereanu, Dulce Brito, Johann Altenberger, Plamen Gatzov, Ivan Milinković, Jaromír Hradec, Jean‐Noel Trochu, Offer Amir, Brenda Moura, Mitja Lainscak, Josep Comin, Gerhard Wikström, Stefan Anker
Journal: European Journal of Heart Failure (2013)
EphA2 Is an Essential Mediator of UV Radiation–Induced Apoptosis
Authors: Guoqi Zhang, Ching-Ni Njauw, Jong Min Park, Chie Naruse, Masahide Asano, Hensin Tsao
Journal: Cancer Research (2008)

Abstract One of the physiologic consequences of excessive UV radiation (UVR) exposure is apoptosis. This critical response serves to eliminate genetically injured cells and arises, in part, from activation of DNA damage and p53 signaling. Other contributory pathways, however, likely exist but have not been fully characterized. In a recent global screen of UVR response genes in melanocytes, we identified the receptor tyrosine kinase EPHA2. Using a combination of genetic and pharmacologic approaches, we set out to investigate the upstream regulation of EphA2 by UVR and the functional consequences of this effect. We found that the UVR-associated increase in EphA2 occurs in melanocytes, keratinocytes, and fibroblasts from both human and murine sources. More specifically, UVR effectively up-regulated EphA2 individually in p53-null, p63-null, and p73-null murine embryonic fibroblasts (MEF), suggesting that the p53 family of transcription factors is not essential for the observed effect. However, inhibition of mitogen-activated protein kinase (MAPK) signaling by U0126 and PD98059 significantly reduced the UVR response whereas overexpression of oncogenic NRAS led to an increase in EphA2. These results confirm that UVR induces EphA2 by a p53-independent, but MAPK-dependent, mechanism. In response to UV irradiation, Epha2−/− MEFs were highly resistant to UVR-mediated cytotoxicity and apoptosis whereas introduction of EphA2 into both wild-type and p53-null MEFs led to activation of an apoptotic program that can be blocked by caspase-8 inhibition. These functional findings suggest that EphA2 is in fact an essential p53-independent, caspase-8–dependent proapoptotic factor induced by UVR. [Cancer Res 2008;68(6):1691–6]
Oncogene-Induced Sensitization to Chemotherapy-Induced Death Requires Induction as well as Deregulation of E2F1
Authors: G. Vignir Helgason, Jim O'Prey, Kevin M. Ryan
Journal: Cancer Research (2010)

Abstract The analysis of DNA tumor viruses has provided landmark insights into the molecular pathogenesis of cancer. A paradigm for this field has been the study of the adenoviral E1a protein, which has led to the identification of proteins such as p300, p400, and members of the retinoblastoma family. Through binding Rb family members, E1a causes deregulation of E2F proteins—an event common to most human cancers and a central pathway in which oncogenes, including E1a, sensitize cells to chemotherapy-induced programmed cell death. We report here, however, that E1a not only causes deregulation of E2F, but importantly that it also causes the posttranscriptional upregulation of E2F1 protein levels. This effect is distinct from the deregulation of E2F1, however, as mutants of E2F1 impaired in pRb binding are induced by E1a and E2F1 induction can also be observed in Rb-null cells. Analysis of E1a mutants selectively deficient in cellular protein binding revealed that induction of E2F1 is instead intrinsically linked to p400. Mutants unable to bind p400, despite being able to deregulate E2F1, do not increase E2F1 protein levels and they do not sensitize cells to apoptotic death. These mutants can, however, be complemented by either the knockdown of p400, resulting in the restoration of the ability to induce E2F1, or by the overexpression of E2F1, with both events reenabling sensitization to chemotherapy-induced death. Due to the frequent deregulation of E2F1 in human cancer, these studies reveal potentially important insights into E2F1-mediated chemotherapeutic responses that may aid the development of novel targeted therapies for malignant disease. Cancer Res; 70(10); 4074–80. ©2010 AACR.
Role of 12-Lipoxygenase in the Stimulation of p38 Mitogen-Activated Protein Kinase and Collagen α5(IV) in Experimental Diabetic Nephropathy and in Glucose-Stimulated Podocytes
Authors: Shin-Wook Kang, Rama Natarajan, Asha Shahed, Cynthia C. Nast, Janine LaPage, Peter Mundel, Clifford Kashtan, Sharon G. Adler
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. The 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism is implicated in extracellular matrix (ECM) synthesis, but its role in podocytes has not been studied. This study tested whether 12-LO induction by diabetes or by high glucose (HG) in cultured podocytes alters glomerular basement membrane by activating signal transduction pathways culminating in ECM synthesis. Sprague-Dawley rats received an injection of diluent (control [C]) or streptozotocin 65 mg/kg (DM) and were killed at 1 or 4 mo. Glomerular 12-LO mRNA and protein levels were higher in DM than in C glomeruli at 1 and 4 mo, and 12-LO localized predominantly in podocytes. Glomerular p38 mRNA and protein were higher in DM at months 1 and 4, but phospho-p38 mitogen-activated protein (MAPK) was increased only at month 1. Glomerular collagen α5(IV)/glutaraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA ratio was increased in DM at month 1 but not at month 4, whereas collagen α5(IV) protein was higher at both 1 and 4 mo. Mouse podocytes were cultured in media with 25 mM glucose (HG) with or without the 12-LO inhibitor cinnamyl-3,4-dihydroxy-cyanocinnamate (CDC) or with 5.5 mM glucose + 19.5 mM mannitol (low glucose [LG+M]) for 10 d at 37°C. 12-LO mRNA and protein levels were higher in HG than in LG+M as was the p38 MAPK/GAPDH mRNA ratio. Phospho-p38 MAPK protein but not total p38 MAPK was higher in HG compared with LG+M. Collagen α5(IV)/GAPDH mRNA ratio and protein were higher in HG than in LG+M. 12-LO inhibition by CDC decreased HG-induced phospho-p38 MAPK and the phospho-p38/total p38 MAPK ratio, collagen α5(IV)/GAPDH mRNA ratio, and collagen α5(IV) protein expression. In summary, diabetes in vivo and exposure of podocytes to HG in vitro stimulated 12-LO, p38 MAPK, and collagen α5(IV) mRNA and (activated) protein. 12-LO inhibition by CDC diminished the expression of podocyte phospho-p38 MAPK and collagen α5(IV) mRNA and protein. These findings implicate 12-LO and the p38 MAPK signaling pathway in the mediation of ECM synthesis by podocytes in diabetes.
Adaptive common carotid arteries remodeling after unilateral internal carotid artery occlusion in adult patients
Authors: N Kubis
Journal: Cardiovascular Research (2001)

This study was undertaken in human adults to examine modifications in common carotid internal diameter (ID), intima-media thickness (IMT), cross-sectional area (CSA) and wall shear stress (WSS) occurring both on the ipsilateral side of an internal carotid artery (ICA) occlusion and on the non-occluded contralateral side.Seventeen patients with unilateral ICA occlusion had repeated echo-Doppler examinations during 1 year and were compared to 12 volunteers with control non-occluded common carotid arteries (CCA).The cause of ICA occlusion was atherosclerosis in nine patients, dissection in five, and undetermined in three. The results showed a significant reduction in ID on the occluded side (5.15 +/- 0.30 mm) compared with the non-occluded side (5.96 +/- 0.20 mm, P < 0.05) and with control arteries (5.55 +/- 0.10, P < 0.05). A significant reduction in blood flow was observed on the occluded side (404 +/- 58 ml/min) compared with the non-occluded side (703 +/- 51 ml/min, P < 0.0001) and with controls (567 +/- 27 ml/min, P < 0.0001). Wall cross-sectional area was found to be positively correlated to blood flow (r = 0.35, P < 0.01), without any significant difference in mean CSA between both sides. Interestingly, wall shear stress values were identical on both sides whatever the cause of ICA occlusion, and did not differ from those in controls.Our results suggest that in humans, the internal diameter of the common carotid artery decreases in response to chronic decrease in blood flow, in order to maintain a constant wall shear stress even in pathological arteries.
Damage to Multicellular Human H-2 Glioma Spheroids Incubated With LAK Cells: An Ultrastructural Study
Authors: J. Jaaskelainen, E. Lehtonen, P. Heikkila, P. Kalliomaki, T. Timonen
Journal: JNCI Journal of the National Cancer Institute (1990)

Local brain tumor therapy using lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) has not proved to be effective in preliminary clinical trials. One obstacle to effective use of this therapy is ignorance about the events that follow contact of the LAK cells with glioma tissue. We used multicellular spheroids grown from human glioma cell lines as targets to study, in vitro, the effect of LAK cells against three-dimensional glioma tissue. Here we describe the ultrastructural changes in spheroids of H-2 glioma cells incubated in pellets of LAK cells for up to 24 hours. In H-2 spheroids, cellular damage was not restricted to the effector cell-target cell (effector-target) contact; it extended farther, at least partly because of nonspecific changes in the spheroid micromilieu. Formation of cytoplasmic blebs, a characteristic effect of T cells, natural killer cells, and LAK cells on single target cells, also occurs in H-2 spheroids, and it is not limited to the effector-target contact area either. These findings suggest that LAK cells release membrane-damaging agents that remain active outside the effector-target area, in the micromilieu of H-2 spheroid tissue.
Rapid Scale-up of Antiretroviral Therapy at Primary Care Sites in Zambia
Authors: Jeffrey S A Stringer, Isaac Zulu, Jens Levy, Elizabeth M Stringer, Albert Mwango, Benjamin H Chi, Vilepe Mtonga, Stewart Reid, Ronald A Cantrell, Marc Bulterys, Michael S Saag, Richard G Marlink, Alwyn Mwinga, Tedd V Ellerbrock, Moses Sinkala
Journal: JAMA (2006)

ContextThe Zambian Ministry of Health has scaled-up human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) care and treatment services at primary care clinics in Lusaka, using predominately nonphysician clinicians.ObjectiveTo report on the feasibility and early outcomes of the program.Design, Setting, and PatientsOpen cohort evaluation of antiretroviral-naive adults treated at 18 primary care facilities between April 26, 2004, and November 5, 2005. Data were entered in real time into an electronic patient tracking system.InterventionThose meeting criteria for antiretroviral therapy (ART) received drugs according to Zambian national guidelines.Main Outcome MeasuresSurvival, regimen failure rates, and CD4 cell response.ResultsWe enrolled 21 755 adults into HIV care, and 16 198 (75%) started ART. Among those starting ART, 9864 (61%) were women. Of 15 866 patients with documented World Health Organization (WHO) staging, 11 573 (73%) were stage III or IV, and the mean (SD) entry CD4 cell count among the 15 336 patients with a baseline result was 143/μL (123/μL). Of 1142 patients receiving ART who died, 1120 had a reliable date of death. Of these patients, 792 (71%) died within 90 days of starting therapy (early mortality rate: 26 per 100 patient-years), and 328 (29%) died after 90 days (post-90-day mortality rate: 5.0 per 100 patient-years). In multivariable analysis, mortality was strongly associated with CD4 cell count between 50/μL and 199/μL (adjusted hazard ratio [AHR], 1.4; 95% confidence interval [CI], 1.0-2.0), CD4 cell count less than 50/μL (AHR, 2.2; 95% CI, 1.5-3.1), WHO stage III disease (AHR, 1.8; 95% CI, 1.3-2.4), WHO stage IV disease (AHR, 2.9; 95% CI, 2.0-4.3), low body mass index (&lt;16; AHR,2.4; 95% CI, 1.8-3.2), severe anemia (&lt;8.0 g/dL; AHR, 3.1; 95% CI, 2.3-4.0), and poor adherence to therapy (AHR, 2.9; 95% CI, 2.2-3.9). Of 11 714 patients at risk, 861 failed therapy by clinical criteria (rate, 13 per 100 patient-years). The mean (SD) CD4 cell count increase was 175/μL (174/μL) in 1361 of 1519 patients (90%) receiving treatment long enough to have a 12-month repeat.ConclusionMassive scale-up of HIV and AIDS treatment services with good clinical outcomes is feasible in primary care settings in sub-Saharan Africa. Most mortality occurs early, suggesting that earlier diagnosis and treatment may improve outcomes.
MOR103, a human monoclonal antibody to granulocyte–macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial
Authors: Frank Behrens, Paul P Tak, Mikkel Østergaard, Rumen Stoilov, Piotr Wiland, Thomas W Huizinga, Vadym Y Berenfus, Stoyanka Vladeva, Juergen Rech, Andrea Rubbert-Roth, Mariusz Korkosz, Dmitriy Rekalov, Igor A Zupanets, Bo J Ejbjerg, Jens Geiseler, Julia Fresenius, Roman P Korolkiewicz, Arndt J Schottelius, Harald Burkhardt
Journal: Annals of the Rheumatic Diseases (2014)

To determine the safety, tolerability and signs of efficacy of MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF), in patients with rheumatoid arthritis (RA).Patients with active, moderate RA were enrolled in a randomised, multicentre, double-blind, placebo-controlled, dose-escalation trial of intravenous MOR103 (0.3, 1.0 or 1.5 mg/kg) once a week for 4 weeks, with follow-up to 16 weeks. The primary outcome was safety.Of the 96 randomised and treated subjects, 85 completed the trial (n=27, 24, 22 and 23 for pooled placebo and MOR103 0.3, 1.0 and 1.5 mg/kg, respectively). Treatment emergent adverse events (AEs) in the MOR103 groups were mild or moderate in intensity and generally reported at frequencies similar to those in the placebo group. The most common AE was nasopharyngitis. In two cases, AEs were classified as serious because of hospitalisation: paronychia in a placebo subject and pleurisy in a MOR103 0.3 mg/kg subject. Both patients recovered fully. In exploratory efficacy analyses, subjects in the MOR103 1.0 and 1.5 mg/kg groups showed significant improvements in Disease Activity Score-28 scores and joint counts and significantly higher European League Against Rheumatism response rates than subjects receiving placebo. MOR103 1.0 mg/kg was associated with the largest reductions in disease activity parameters.MOR103 was well tolerated and showed preliminary evidence of efficacy in patients with active RA. The data support further investigation of this monoclonal antibody to GM-CSF in RA patients and potentially in those with other immune-mediated inflammatory diseases.NCT01023256.