tbuckley/cabot-search huggingface dataset:
Angiotensin II-aldosterone interaction in human coronary microarteries involves GPR30, EGFR, and endothelial NO synthase
Authors: W. W. Batenburg, P. M. Jansen, A. J. van den Bogaerdt, A. H. J. Danser
Journal: Cardiovascular Research (2012)

The aim of this study was to investigate the aldosterone–angiotensin (Ang) II interaction in human coronary microarteries (HCMAs). HCMAs, obtained from 75 heart-beating organ donors, were mounted in myographs and exposed to Ang II, either directly or following a 30-min pre-incubation with aldosterone, 17β-oestradiol, hydrocortisone, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580, the extracellular regulated kinase 1/2 (ERK1/2) inhibitor PD98059, the GPR30 antagonist G15, or the epidermal growth factor receptor (EGFR) antagonist AG1478. Ang II constricted HCMAs in a concentration-dependent manner. All steroids, at nanomolar levels, potentiated Ang II and G15 prevented this effect. The potentiation disappeared or was reversed into Ang II antagonism at micromolar steroid levels. NO synthase (NOS) inhibition prevented the latter antagonism in the case of 17β-oestradiol, whereas both aldosterone and 17β-oestradiol at micro- (but not nano-) molar levels induced endothelial NOS phosphorylation in human umbilical vein endothelial cells. AG1478, but not SB203580 or PD98059, abolished the Ang II-induced contraction in the presence of aldosterone or 17β-oestradiol, and none of these drugs affected Ang II alone. Steroids including aldosterone affect Ang II-induced vasoconstriction in a biphasic manner. Potentiation occurs at nanomolar steroid levels and depends on GPR30 and EGFR transactivation. At micromolar steroid levels, this potentiation either disappears (aldosterone and hydrocortisone) or is reversed into an inhibition (17β-oestradiol), and this is due to the endothelial NOS activation that occurs at such concentrations.
Reduced CD36-dependent tissue sequestration of <i>Plasmodium</i>-infected erythrocytes is detrimental to malaria parasite growth in vivo
Authors: Jannik Fonager, Erica M. Pasini, Joanna A.M. Braks, Onny Klop, Jai Ramesar, Edmond J. Remarque, Irene O.C.M. Vroegrijk, Sjoerd G. van Duinen, Alan W. Thomas, Shahid M. Khan, Matthias Mann, Clemens H.M. Kocken, Chris J. Janse, Blandine M.D. Franke-Fayard
Journal: The Journal of Experimental Medicine (2011)

Adherence of parasite-infected red blood cells (irbc) to the vascular endothelium of organs plays a key role in the pathogenesis of Plasmodium falciparum malaria. The prevailing hypothesis of why irbc adhere and sequester in tissues is that this acts as a mechanism of avoiding spleen-mediated clearance. Irbc of the rodent parasite Plasmodium berghei ANKA sequester in a fashion analogous to P. falciparum by adhering to the host receptor CD36. To experimentally determine the significance of sequestration for parasite growth, we generated a mutant P. berghei ANKA parasite with a reduced CD36-mediated adherence. Although the cognate parasite ligand binding to CD36 is unknown, we show that nonsequestering parasites have reduced growth and we provide evidence that in addition to avoiding spleen removal, other factors related to CD36-mediated sequestration are beneficial for parasite growth. These results reveal for the first time the importance of sequestration to a malaria infection, with implications for the development of strategies aimed at reducing pathology by inhibiting tissue sequestration.
Optimizing Cancer Treatments to Induce an Acute Immune Response: Radiation Abscopal Effects, PAMPs, and DAMPs
Authors: Charles M. Ludgate
Journal: Clinical Cancer Research (2012)

Abstract Clinical results indicate improved survival in poorly differentiated prostate cancer patients following a treatment schedule that maximizes hormone therapy prior to radiation. This may be because of a systemic immune response, called an abscopal effect. A literature review showed an association between acute infection and abscopal cancer remission. This led to the theory that, in the presence of endogenous cancer-specific antigens exposed by cancer necrosis, an innate immune response can adapt to respond to those antigens via a cross-talk mechanism. This theory was validated in an animal model. An acute innate immune T-cell response was stimulated using cluster vaccination with Poly(I:C). In the presence of exogenous cancer-specific antigens, this immune response became adaptive, creating an abscopal effect that resulted in cancer resolution. These concepts may be of clinical value, improving outcomes by inducing systemic abscopal effects. Clin Cancer Res; 18(17); 4522–5. ©2012 AACR.
Different Roles of Estrogen Receptors α and β in the Regulation of E-Cadherin Protein Levels in a Mouse Mammary Epithelial Cell Line
Authors: Luisa A. Helguero, Karolina Lindberg, Cissi Gardmo, Thomas Schwend, Jan-Åke Gustafsson, Lars-Arne Haldosén
Journal: Cancer Research (2008)

Abstract Two estrogen receptors (ERα and ERβ) are found throughout the mammary gland. Evidence indicates that, while ERα transduces proliferation signals, ERβ opposes this effect and is necessary for epithelial differentiation. Using mouse mammary epithelial cells, we have previously shown that activation of ERβ opposes ERα-induced proliferation and increases apoptosis. Furthermore, stable knockdown of ERβ resulted in loss of growth contact inhibition. In this work, we report that loss of ERβ is associated with a decrease of E-cadherin protein levels through different posttranscriptional regulatory mechanisms. Ligand activation of ERα induced E-cadherin extracellular shedding and internalization only in the absence of ERβ, followed by lysosomal degradation. Loss of ERβ also led to an increase of E-cadherin uptake in a ligand-independent manner through mechanisms that required caveolae formation. Proteasome activity was necessary for both mechanisms to operate. Increased E-cadherin internalization correlated with the up-regulation of β-catenin transcriptional activity and impaired morphogenesis on Engelbreth-Holm-Swarm matrix. Taken together, these results emphasize the role of epithelial ERβ in maintaining cell adhesion and a differentiated phenotype and highlight the potential importance of ERβ for the design of specific agonists for use in breast cancer therapy. [Cancer Res 2008;68(21):8695–704]
Newly diagnosed HIV infections: review in UK and Ireland
Authors: Ann K Sullivan, Hilary Curtis, Caroline A Sabin, Margaret A Johnson
Journal: BMJ (2005)

In 2001, 59% of people in the United Kingdom with HIV who were starting treatment had CD4 lymphocyte counts of fewer than 200 cells/ l, 1 mostly because of late diagnosis.We investigated new HIV diagnoses in the UK and Ireland, to assess the occurrence of late diagnosis (CD4 lymphocyte count < 200cells/ l) and associated features and to determine if patients had prior presentations that may have been related to HIV infection. Participants, methods, and resultsWe did a national case review by sending structured questionnaire forms to adult HIV care providers in the United Kingdom and Ireland for patients presenting with a new diagnosis of HIV infection in January-March 2003 (maximum of 25 per centre).We collected information on clinical and immune status and hospital admissions and symptoms or conditions in the previous 12 months that might have been HIV related.Of 148 centres, 113 (76%) responded with data on 977 patients.Overall, 301 (33%) presented late (table), and this was more common in older patients (adjusted odds ratio per increase in age group 1.68, 95% confidence interval 1.42 to 1.98; P = 0.0001) and in black Africans (1.66, 1.05 to 2.62, P = 0.03), but less likely in homosexual men, independent of age and ethnicity (0.63, 0.38 to 1.05, P = 0.07).Overall, 401 (41%) were diagnosed via routine screening; this was
P62dok, a Negative Regulator of Ras and Mitogen-Activated Protein Kinase (Mapk) Activity, Opposes Leukemogenesis by P210bcr-abl
Authors: Antonio Di Cristofano, Masaru Niki, Mingming Zhao, Fredrick G. Karnell, Bayard Clarkson, Warren S. Pear, Linda Van Aelst, Pier Paolo Pandolfi
Journal: The Journal of Experimental Medicine (2001)

p62dok has been identified as a substrate of many oncogenic tyrosine kinases such as the chronic myelogenous leukemia (CML) chimeric p210bcr-abl oncoprotein. It is also phosphorylated upon activation of many receptors and cytoplamic tyrosine kinases. However, the biological functions of p62dok in normal cell signaling as well as in p210bcr-abl leukemogenesis are as yet not fully understood. Here we show, in hemopoietic and nonhemopoietic cells derived from p62dok−/− mice, that the loss of p62dok results in increased cell proliferation upon growth factor treatment. Moreover, Ras and mitogen-activated protein kinase (MAPK) activation is markedly sustained in p62dok−/− cells after the removal of growth factor. However, p62dok inactivation does not affect DNA damage and growth factor deprivation–induced apoptosis. Furthermore, p62dok inactivation causes a significant shortening in the latency of the fatal myeloproliferative disease induced by retroviral-mediated transduction of p210bcr-abl in bone marrow cells. These data indicate that p62dok acts as a negative regulator of growth factor–induced cell proliferation, at least in part through downregulating Ras/MAPK signaling pathway, and that p62dok can oppose leukemogenesis by p210bcr-abl.
Novel Protein Genes in Animal mtDNA: A New Sex Determination System in Freshwater Mussels (Bivalvia: Unionoida)?
Authors: Sophie Breton, Donald T. Stewart, Sally Shepardson, Richard J. Trdan, Arthur E. Bogan, Eric G. Chapman, Andrew J. Ruminas, Helen Piontkivska, Walter R. Hoeh
Journal: Molecular Biology and Evolution (2010)

Mitochondrial (mt) function depends critically on optimal interactions between components encoded by mt and nuclear DNAs. mitochondrial DNA (mtDNA) inheritance (SMI) is thought to have evolved in animal species to maintain mito-nuclear complementarity by preventing the spread of selfish mt elements thus typically rendering mtDNA heteroplasmy evolutionarily ephemeral. Here, we show that mtDNA intraorganismal heteroplasmy can have deterministic underpinnings and persist for hundreds of millions of years. We demonstrate that the only exception to SMI in the animal kingdom, that is, the doubly uniparental mtDNA inheritance system in bivalves, with its three-way interactions among egg mt-, sperm mt- and nucleus-encoded gene products, is tightly associated with the maintenance of separate male and female sexes (dioecy) in freshwater mussels. Specifically, this mother-through-daughter and father-through-son mtDNA inheritance system, containing highly differentiated mt genomes, is found in all dioecious freshwater mussel species. Conversely, all hermaphroditic species lack the paternally transmitted mtDNA (=possess SMI) and have heterogeneous macromutations in the recently discovered, novel protein-coding gene (F-orf) in their maternally transmitted mt genomes. Using immunoelectron microscopy, we have localized the F-open reading frame (ORF) protein, likely involved in specifying separate sexes, in mitochondria and in the nucleus. Our results support the hypothesis that proteins coded by the highly divergent maternally and paternally transmitted mt genomes could be directly involved in sex determination in freshwater mussels. Concomitantly, our study demonstrates novel features for animal mt genomes: the existence of additional, lineage-specific, mtDNA-encoded proteins with functional significance and the involvement of mtDNA-encoded proteins in extra-mt functions. Our results open new avenues for the identification, characterization, and functional analyses of ORFs in the intergenic regions, previously defined as "noncoding," found in a large proportion of animal mt genomes.
THE RADIATIONAL TREATMENT OF CORNEAL ULCERS
Authors: W. S. Duke-Elder
Journal: BMJ (1929)

MThzB1iyT 41 most part, in the "larval " rather than in the " compen- sated " phase of latent tuberculosis.This is a situation Whiclh is likely to reproduce itself in the more recently occupied parts of Africa as weU as in other countries where hitherto isolated coimmnunities are being brought into in- creasinig colitact with Europeani civilization.It would be IN-ell if inidustrialists in such countries studied the methods of prevention airived at, tlhroughi long experience, by the Johannesburg Chamber of Mines.The importance of a correct appreciationi of the factors underlyinig the phenomena of tuberculosis in "v-irgin soil- and after " is not, theln, confined to the management of children and adolescents in this country, but has a wide bearing upon the future of industrial populatiolns in our dominions, colonies, and dependencies.I hope that the suggestions here set forth, but for which no originalitv is-claimed, may serve to stimulnlate further thouglit and further investigation into somie of the basic problems of our most formidable bacteri-al disease.
Intravenous Iloprost Infusion in Patients with Raynaud Phenomenon Secondary to Systemic Sclerosis: A Multicenter, Placebo-controlled, Double-Blind Study
Authors: Fredrick M. Wigley
Journal: Annals of Internal Medicine (1994)

Objective: To evaluate the efficacy and safety of iloprost, a prostacyclin analog, administered intravenously in patients with Raynaud phenomenon secondary to systemic sclerosis. Design: Multicenter, randomized, parallel placebo-controlled, double-blind study. Setting: University medical centers. Patients: 131 patients with systemic sclerosis (101 women, 30 men) ages 20 to 79 years. Intervention: Patients were randomly assigned to receive one of two parallel treatments of five daily sequential, 6-hour intravenous infusions of iloprost (0.5 to 2.0 ng/kg per min) or to receive a similar volume of placebo. Measurements: Frequency of Raynaud attacks, Raynaud severity score, physician's overall rating of treatment effect, and digital cutaneous lesion healing. Results: Of the 131 patients enrolled, 126 completed the 5-day infusion and 114 (87%) completed at least 6 weeks of follow-up. Sixty-four patients were randomly assigned to receive iloprost and 67 patients, to receive placebo. The mean weekly number of Raynaud attacks decreased 39.1% with iloprost and 22.2% with placebo (P = 0.005). In addition, the mean percentage of improvement in a global Raynaud severity score during the entire 9-week follow-up was greater in patients given iloprost (34.8%) than in those receiving placebo (19.7%) (P = 0.011). The physician's overall rating of treatment effect showed greater improvement with iloprost than with placebo at week 6 (52.4% compared with 27.4%; P = 0.008) and week 9 (60.9% compared with 26.9%; P < 0.001). At week 3, 14.6% more patients receiving iloprost had 50% or more lesions heal compared with those given placebo (95% CI, 0.9% to 30%). During the infusion, 59 (92%) of the patients receiving iloprost had one or more side effects compared with 38 (57%) of the patients receiving placebo. Conclusion: Iloprost is effective for the short-term palliation of severe Raynaud phenomenon in patients with systemic sclerosis.
Lung function in the children of immigrant and UK-born south-Asian mothers
Authors: Claudia E. Kuehni, Marie-Pierre F. Strippoli, Ben D. Spycher, Michael Silverman, Caroline S. Beardsmore
Journal: European Respiratory Journal (2015)

There are ethnic differences in lung function, with white subjects having larger height-normalised forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) than black people or Asians [1, 2]. It has been argued that these differences might be explained by environmental and social factors associated with poverty [3, 4]. Alternatively, the differences in lung volume might be explained by inherent factors, such as genetically determined differences in body frame, with a relatively smaller thoracic cage and, consequently, smaller lungs in some Asian ethnic groups [4, 5]. If the differences were explained mainly or entirely by environmental exposures, lung function in populations migrating from a south-Asian to a western European country should increase in successive generations as standards of living gradually approach those of the host region. Lung function is similarly low in children of migrant and UK-born south-Asian mothers <http://ow.ly/Fhs4e> We thank the parents and children of Leicestershire and Rutland, UK, for participating, and Tony Davis (Specialist Community Child Health Services, Leicester City Primary Care Trust, Leicester, UK) for his assistance.
Association study of<i>BAK1</i>gene polymorphisms in Spanish rheumatoid arthritis and systemic lupus erythematosus cohorts
Authors: Lina-Marcela Díaz-Gallo, Sonia Garcia, Norberto Ortego-Centeno, Juan Jiménez-Alonso, Julio Sánchez-Román, Enrique de Ramón, María F González-Escribano, Alejandro Balsa, Benjamín Fernández-Gutierrez, Isidoro González-Alvaro, Miguel A González-Gay, Javier Martin
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> To determine whether inhibition of p38 mitogen-activated protein kinase (p38MAPK) reduces the pathogenicity of anti-neutrophil cytoplasmic autoantibodies (ANCAs) in vitro and in vivo. <h3>Methods</h3> The effects of the p38MAPK-specific inhibitor AR-447 were studied in vitro using neutrophil respiratory burst and degranulation assays, and in lipopolysaccharide (LPS)-stimulated human glomerular endothelial cells. In vivo, p38MAPK inhibition was investigated in a mouse anti-myeloperoxidase (MPO) IgG/LPS glomerulonephritis model. Mice were treated orally with AR-447 daily, starting before (pretreatment group) or 24 h after disease onset (treatment group), and killed after 1 or 7 day(s). <h3>Results</h3> In vitro, AR-447 diminished neutrophil respiratory burst and degranulation induced by patient-derived MPO-ANCA and proteinase 3 (Pr3)-ANCA. In glomerular endothelial cells, AR-447 reduced LPS-induced secretion of IL-6 and IL-8, but not of MCP-1. In mice, pretreatment with AR-447 reduced albuminuria 1 day after induction of glomerulonephritis. After 7 days, no effects on urinary abnormalities were observed upon AR-447 pretreatment or treatment. Also, glomerular neutrophil accumulation was not diminished. In contrast, glomerular macrophage accumulation and the formation of glomerular crescents was significantly reduced by AR-447 pretreatment (vehicle: 12.5 ± 5.6% crescentic glomeruli; AR-447: 7.7 ± 2.7%) and treatment (vehicle 14.6 ± 1.8%; AR-447 6.0 ± 3.4%) at 7 days. <h3>Conclusion</h3> This study shows that p38MAPK inhibition markedly reduces ANCA-induced neutrophil activation in vitro. In vivo, p38MAPK inhibition partly reduced crescent formation when the drug was administered prior to disease induction and after disease onset, suggesting that besides p38MAPK activity other signalling pathways contribute to the disease activity.
The impact of smoking cessation on respiratory symptoms, lung function, airway hyperresponsiveness and inflammation
Authors: B.W.M. Willemse, D.S. Postma, W. Timens, N.H.T. ten Hacken
Journal: European Respiratory Journal (2004)

Smoking is the main risk factor in the development of chronic obstructive pulmonary disease (COPD), and smoking cessation is the only effective treatment for avoiding or reducing the progression of this disease. Despite the fact that smoking cessation is a very important health issue, information about the underlying mechanisms of the effects of smoking cessation on the lungs is surprisingly scarce. It is likely that the reversibility of smoke-induced changes differs between smokers without chronic symptoms, smokers with nonobstructive chronic bronchitis and smokers with COPD. This review describes how these three groups differ regarding the effects of smoking cessation on respiratory symptoms, lung function (forced expiratory volume in one second), airway hyperresponsiveness, and pathological and inflammatory changes in the lung. Smoking cessation clearly improves respiratory symptoms and bronchial hyperresponsiveness, and prevents excessive decline in lung function in all three groups. Data from well-designed studies are lacking regarding the effects on inflammation and remodelling, and the few available studies show contradictory results. In chronic obstructive pulmonary disease, a few histopathological studies suggest that airway inflammation persists in exsmokers. Nevertheless, many studies have shown that smoking cessation improves the accelerated decline in forced expiratory volume in one second, which strongly indicates that important inflammatory and/or remodelling processes are positively affected.
Normalized Diastolic Properties After Left Ventricular Assist Result From Reverse Remodeling of Chamber Geometry
Authors: Alessandro Barbone, Mehmet C. Oz, Daniel Burkhoff, Jeffrey W. Holmes
Journal: Circulation (2001)

Normalization of diastolic properties after left ventricular (LV) assist may result from a change in myocardial material properties, chamber size, or both. This study tested the hypothesis that reported normalization of LV diastolic properties is primarily due to remodeling of chamber geometry.Hearts were obtained at transplantation from 8 patients with dilated cardiomyopathy (DCM), 6 patients with DCM plus 33+/-5 days of LV assist, and 3 patients with no evidence of heart failure. LV assist normalized passive pressure-volume curves. Chamber dimensions decreased without a change in the ratio of radius to wall thickness. Midwall stress-stretch relations predicted from pressure-volume and dimension data were not different for DCM and LV assist hearts. Passive stress-stretch relations were measured in endocardial trabeculae and were not different for DCM and LV assist hearts. Myocyte size and collagen area fraction were unchanged at this brief duration of support.These findings are all consistent with the hypothesis that early normalization of diastolic properties after LV assist device support results from remodeling of chamber geometry, not from changes in tissue stiffness. These data emphasize the importance of geometry to ventricular mechanics and demonstrate that reduction of heart size does not necessarily produce a reduction in wall stress.
Identification of a Crohn’s disease specific transcript with potential as a diagnostic marker
Authors: D A Lafontaine, S Mercure, J-P Perreault
Journal: Gut (1998)

Background —A long time goal of the medical research community has been the identification of a reliable and valid marker for Crohn’s disease. Aim —To identify differences in the genetic expression patterns of healthy and diseased tissues. Method —The RNA arbitrarily primed polymerase chain reaction (RAP-PCR) procedure was modified to improve its potential to identify clinical markers in heterogeneous RNA populations. Results —With this procedure, a 1065 bp PCR product associated with the inflammation that occurs in Crohn’s disease was identified, cloned and sequenced. Northern blot hybridisations showed that this novel sequence originates from a unique RNA species of 3.1 kb. Dot blot hybridisations clearly showed that this RNA species was specific to Crohn’s disease. Moreover, its abundance seemed to correlate with the severity of inflammation. Finally, this RNA species was also detected in macroscopically normal areas from Crohn’s disease specimens, suggesting that it appears either early during the disease or at least before severe manifestations. Conclusion —This finding of a 3.1 kb RNA species permits the discrimination of Crohn’s disease manifestations. Although further clinical work is required, this transcript appears to have definite potential as a diagnostic marker.