tbuckley/cabot-search huggingface dataset:
Oxidative Stress and Response in Relation to Coronary Artery Disease in Type 1 Diabetes
Authors: Tina Costacou, Rhobert W. Evans, Gerald L. Schafer, Trevor J. Orchard
Journal: Diabetes Care (2013)

Although oxidative stress (OxS) is thought to contribute to atherosclerosis and coronary artery disease (CAD), little is known about the variability in an individual's ability to respond to OxS. Therefore, we assessed potential indices of response to OxS and evaluated whether they modify the association between OxS and CAD.We evaluated plasma α- and γ-tocopherol per unit cholesterol (potential response markers); urinary 15-isoprostane F2t per milligram creatinine (isoprostane [IsoP], a potential stress marker); and the α-tocopherol-to-IsoP ratio (as a measure of response to stress), measured three times during 20 years of follow-up, in relation to CAD incidence in a cohort with childhood-onset type 1 diabetes (n = 658; mean age at baseline, 28 years; duration of diabetes, 19 years). Participants with three samples (blood and either 24-h or overnight urine) available before the onset of CAD or the end of follow-up (n = 356) were selected for study.In multivariable mixed models, α-tocopherol over time was inversely associated with CAD (β = -0.27; P = 0.02), whereas a direct association was observed for IsoP (β = 0.0008; P = 0.06). Moreover, the α-tocopherol-to-IsoP ratio was strongly and inversely related to CAD incidence (β = -0.72; P = 0.003), whereas in a separate model including α-tocopherol and IsoP, both biomarkers maintained statistical significance. No association was observed for γ-tocopherol (β = -0.22; P = 0.54).These data suggest that a greater potential capability (α-tocopherol) to respond to OxS (urinary IsoP) relates to CAD incidence.
Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction
Authors: Gilles Montalescot, Arnoud W. van 't Hof, Frédéric Lapostolle, Johanne Silvain, Jens Flensted Lassen, Leonardo Bolognese, Warren J. Cantor, Ángel Cequier, Mohamed Chettibi, Shaun G. Goodman, Christopher J. Hammett, Kurt Huber, Magnus Janzon, Béla Merkely, Robert F. Storey, Uwe Zeymer, Olivier Stibbe, Patrick Ecollan, Wim M.J.M. Heutz, Eva Swahn, Jean-Philippe Collet, Frank F. Willems, Caroline Baradat, Muriel Licour, Anne Tsatsaris, Eric Vicaut, Christian W. Hamm
Journal: New England Journal of Medicine (2014)

The direct-acting platelet P2Y12 receptor antagonist ticagrelor can reduce the incidence of major adverse cardiovascular events when administered at hospital admission to patients with ST-segment elevation myocardial infarction (STEMI). Whether prehospital administration of ticagrelor can improve coronary reperfusion and the clinical outcome is unknown.
Expression of the ELAV-Like Protein HuR Is Associated with Higher Tumor Grade and Increased Cyclooxygenase-2 Expression in Human Breast Carcinoma
Authors: Carsten Denkert, Wilko Weichert, Klaus-Jürgen Winzer, Berit-Maria Müller, Aurelia Noske, Silvia Niesporek, Glen Kristiansen, Hans Guski, Manfred Dietel, Steffen Hauptmann
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The human ELAV (embryonic lethal abnormal vision)-like protein HuR stabilizes a certain group of cellular mRNAs that contain AU-rich elements in their 3′-untranslated region. Cell culture studies have shown that the mRNA of cyclooxygenase (COX)-2 can be stabilized by HuR. Experimental Design: To investigate a possible contribution of dysregulation of mRNA stability to the progression of cancer and to overexpression of COX-2, we studied expression of HuR in 208 primary breast carcinomas by immunohistochemistry. Results: There were two different staining patterns of HuR in tumor tissue of breast carcinomas: nuclear expression was seen in 61% of cases; and an additional cytoplasmic expression was seen in 30% of cases. Expression of HuR was significantly associated with increased COX-2 expression; this association was particularly significant for cytoplasmic HuR expression (P &amp;lt; 0.0005). We further observed a significant association of cytoplasmic (P = 0.002) or nuclear HuR (P = 0.027) expression with increased tumor grade. Only 13% of the grade 1 carcinomas showed cytoplasmic expression of HuR, compared with 46% of the grade 3 carcinomas. There was no significant correlation between HuR expression and other clinicopathological parameters such as histological type, tumor size, or nodal status as well as patient survival. Conclusions: Our results suggest that overexpression of HuR in tumor tissue may be part of a regulatory pathway that controls the mRNA stability of several important targets in tumor biology, such as COX-2. Based on our results, additional studies are necessary to investigate whether HuR might be a potential target for molecular tumor therapy.
Effect of Exenatide, Sitagliptin, or Glimepiride on β-Cell Secretory Capacity in Early Type 2 Diabetes
Authors: Lalitha Gudipaty, Nora K. Rosenfeld, Carissa S. Fuller, Robert Gallop, Mark H. Schutta, Michael R. Rickels
Journal: Diabetes Care (2014)

OBJECTIVE Agents that augment GLP-1 effects enhance glucose-dependent β-cell insulin production and secretion and thus are hoped to prevent progressive impairment in insulin secretion characteristic of type 2 diabetes (T2D). The purpose of this study was to evaluate GLP-1 effects on β-cell secretory capacity, an in vivo measure of functional β-cell mass, early in the course of T2D. RESEARCH DESIGN AND METHODS We conducted a randomized controlled trial in 40 subjects with early T2D who received the GLP-1 analog exenatide (n = 14), the dipeptidyl peptidase IV inhibitor sitagliptin (n = 12), or the sulfonylurea glimepiride (n = 14) as an active comparator insulin secretagogue for 6 months. Acute insulin responses to arginine (AIRarg) were measured at baseline and after 6 months of treatment with 5 days of drug washout under fasting, 230 mg/dL (glucose potentiation of arginine-induced insulin release [AIRpot]), and 340 mg/dL (maximum arginine-induced insulin release [AIRmax]) hyperglycemic clamp conditions, in which AIRmax provides the β-cell secretory capacity. RESULTS The change in AIRpot was significantly greater with glimepiride versus exenatide treatment (P &amp;lt; 0.05), and a similar trend was notable for the change in AIRmax (P = 0.1). Within each group, the primary outcome measure, AIRmax, was unchanged after 6 months of treatment with exenatide or sitagliptin compared with baseline but was increased with glimepiride (P &amp;lt; 0.05). α-Cell glucagon secretion (AGRmin) was also increased with glimepiride treatment (P &amp;lt; 0.05), and the change in AGRmin trended higher with glimepiride than with exenatide (P = 0.06). CONCLUSIONS After 6 months of treatment, exenatide or sitagliptin had no significant effect on functional β-cell mass as measured by β-cell secretory capacity, whereas glimepiride appeared to enhance β- and α-cell secretion.
Physical activity and coronary heart disease
Authors: G David Batty, I-Min Lee
Journal: BMJ (2004)

general secretary, for assisted suicide prompted the organisation to change its name from EXIT, in order to distance itself from his activities. 5Then as now the organisation clearly stated that it does not condone operating outside the law, although it does seek a change in the law.Surely a case is to be made for reform, but not along the permissive lines that have been proposed, including those in a controversial editorial in this journal. 6Rather, what is needed is greater clarity in the definition and application of the offence.The prosecutions to date in England and Wales show a body of law that is replete with uncertainty, obfuscation, and injustice.Consider the "classic" case of "leaving the pills."Certainly convictions have been made in such circumstances, but this does not explain why one case was dismissed by the court since the accused "only provided the option," which was, said the judge, "not enough." 7 Furthermore no health professional has been prosecuted for the offence in this jurisdiction despite at least anecdotal evidence indicating that such assistance does occur. 8o less confusing is the (il)legality of "death tourism."After Reginald Crew was assisted to die in Switzerland, uncertainty prevailed over whether his wife, Win, had committed an offence in helping him to travel there.Although the police declined to prosecute in that case, they have yet to promulgate their prosecuting policy on this issue.
Maternal embryonic leucine zipper kinase enhances gastric cancer progression via the FAK/Paxillin pathway
Authors: Tao Du, Ying Qu, Jianfang Li, Hao Li, Liping Su, Quan Zhou, Min Yan, Chen Li, Zhenggang Zhu, Bingya Liu
Journal: Molecular Cancer (2014)

Elevated MELK expression is featured in multiple tumors and correlated with tumorigenesis and tumor development. This study is aimed to investigate the mechanisms of MELK-mediated development of gastric cancer. MELK expression levels in human gastric cancer were determined by quantitative-PCR and immunohistochemistry. The effect of MELK on cell activity was explored by knockdown and overexpression experiments. Cell growth was measured using the CCK-8 assay. Apoptosis and cell cycle distributions were analyzed by flow cytometry. Migration and invasion were tested using a transwell migration assay. Cytoskeletal changes were analyzed by immunofluorescence. To explore the molecular mechanism and effect of MELK on migration and invasion, Western blotting was used to analyze the FAK/Paxillin pathway and pull down assays for the activity of small Rho GTPases. In vivo tumorigenicity and peritoneal metastasis experiments were performed by tumor cell engraftment into nude mice. MELK mRNA and protein expression were both elevated in human gastric cancer, and this was associated with chemoresistance to 5-fluorouracil (5-FU). Knockdown of MELK significantly suppressed cell proliferation, migration and invasion of gastric cancer both in vitro and in vivo, decreased the percentages of cells in the G1/G0 phase and increased those in the G2/M and S phases. Moreover, knockdown of MELK decreased the amount of actin stress fibers and inhibited RhoA activity. Finally, knockdown of MELK decreased the phosphorylation of the FAK and paxillin, and prevented gastrin-stimulated FAK/paxillin phosphorylation. By contrast, MELK overexpression had the opposite effect. MELK promotes cell migration and invasion via the FAK/Paxillin pathway, and plays an important role in the occurrence and development of gastric cancer. MELK may be a potential target for treatment against gastric cancer.
Complement Activation in Patients With Congestive Heart Failure
Authors: Pål Aukrust, Lars Gullestad, Knut T. Lappegård, Thor Ueland, Halfdan Aass, Lisbeth Wikeby, Svein Simonsen, Stig S. Frøland, Tom E. Mollnes
Journal: Circulation (2001)

Background Increasing evidence implicates innate immunity in the pathogenesis of congestive heart failure (CHF). In the present study, we examined the possible role of complement, an important part of innate immunity, in CHF. Methods and Results Complement activation was analyzed in systemic and coronary circulation in 39 patients with CHF and 20 healthy control subjects. In a double-blind, placebo-controlled study, we have recently reported that high-dose intravenous immunoglobulin (IVIG) improves left ventricular ejection fraction (LVEF) in these patients. To examine if this improvement was related to IVIG-induced effects on complement, we also examined complement activation during induction (first week) and maintenance therapy (6 months) with IVIG or placebo. Our main findings were: (1) We found enhanced systemic complement activation involving classic, alternative, as well as terminal pathway in patients with CHF compared with healthy control subjects. (2) Particularly enhanced complement activation was found in coronary sinus, representing venous drainage from the heart. (3) The systemic complement activation was further enhanced during IVIG but not during placebo therapy, particularly during induction therapy. (4) Although IVIG improved LVEF in patients with CHF, the degree of IVIG-mediated complement activation was negatively correlated with this improvement of LVEF. Conclusions This study further supports the involvement of innate immunity in the pathogenesis of CHF. Our findings suggest that complement may be added to the list of possible therapeutic targets in CHF and that future studies with specific complement inhibitors may be of interest in this disorder.
Musings on genome medicine: enzyme-replacement therapy of the lysosomal storage diseases
Authors: David G Nathan, Stuart H Orkin
Journal: Genome Medicine (2009)

The lysosomal storage diseases, such as Gaucher's disease, mucopolysaccharidosis I, II and IV, Fabry's disease, and Pompe's disease, are rare inherited disorders whose symptoms result from enzyme deficiency causing lysosomal accumulation. Until effective gene-replacement therapy is developed, expensive, and at best incomplete, enzyme-replacement therapy is the only hope for sufferers of rare lysosomal storage diseases. Preventive strategies involving carrier detection should be a priority toward the successful management of these conditions.
Pleural innate response activator B cells protect against pneumonia via a GM-CSF-IgM axis
Authors: Georg F. Weber, Benjamin G. Chousterman, Ingo Hilgendorf, Clinton S. Robbins, Igor Theurl, Louisa M.S. Gerhardt, Yoshiko Iwamoto, Tam D. Quach, Muhammad Ali, John W. Chen, Thomas L. Rothstein, Matthias Nahrendorf, Ralph Weissleder, Filip K. Swirski
Journal: The Journal of Experimental Medicine (2014)

Pneumonia is a major cause of mortality worldwide and a serious problem in critical care medicine, but the immunophysiological processes that confer either protection or morbidity are not completely understood. We show that in response to lung infection, B1a B cells migrate from the pleural space to the lung parenchyma to secrete polyreactive emergency immunoglobulin M (IgM). The process requires innate response activator (IRA) B cells, a transitional B1a-derived inflammatory subset which controls IgM production via autocrine granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling. The strategic location of these cells, coupled with the capacity to produce GM-CSF–dependent IgM, ensures effective early frontline defense against bacteria invading the lungs. The study describes a previously unrecognized GM-CSF-IgM axis and positions IRA B cells as orchestrators of protective IgM immunity.
Evidence from Beta-Tubulin Phylogeny that Microsporidia Evolved from Within the Fungi
Authors: Patrick J. Keeling, Melissa A. Luker, Jeffrey D. Palmer
Journal: Molecular Biology and Evolution (2000)

Microsporidia are obligate intracellular parasites that were thought to be an ancient eukaryotic lineage based on molecular phylogenies using ribosomal RNA and translation elongation factors. However, this ancient origin of microsporidia has been contested recently, as several other molecular phylogenies suggest that microsporidia are closely related to fungi. Most of the protein trees that place microsporidia with fungi are not well sampled, however, and it is impossible to resolve whether microsporidia evolved from a fungus or from a protistan relative of fungi. We have sequenced beta-tubulins from 3 microsporidia, 4 chytrid fungi, and 12 zygomycete fungi, expanding the representation of beta-tubulin to include all four fungal divisions and a wide diversity of microsporidia. In phylogenetic trees including these new sequences, the overall topology of the fungal beta-tubulins generally matched the expected relationships among the four fungal divisions, although the zygomycetes were polyphyletic in some analyses. The microsporidia consistently fell within this fungal diversification, and not as a sister group to fungi. Overall, beta-tubulin phylogeny suggests that microsporidia evolved from a fungus sometime after the divergence of chytrids. We also found that chytrid alpha- and beta-tubulins are much less divergent than are tubulins from other fungi or microsporidia. In trees in which the only fungal representatives were the chytrids, microsporidia still branched with fungi (i.e., with chytrids), suggesting that the affiliation between microsporidian and fungal tubulins is not an artifact of long-branch attraction.
Changes in the bidirectional sodium flux across the intestinal mucosa in Crohn's disease.
Authors: R Allan, D M Steinberg, K Dixon, W T Cooke
Journal: Gut (1975)

Bidirectional sodium flux across the intestinal mucosa was measured in a group of 10 patients with Crohn's disease treated in the past by panproctocolectomy with ileostomy and compared with a similarly treated group of 11 patients with ulcerative colitis. All of them were in good health at the time of the study and a recent radiological examination of the small intestine was normal. A significant reduction in bidirectional sodium flux was found in those patients with Crohn's disease and suggests that the intestinal mucosa is involved to a greater extent than can be judged by radiological appearances alone. This adds weight to the concept that Crohn's diseases is a diffuse rather than a focal lesion of the gastrointestinal tract.
Randomised controlled trial of lymphoblastoid interferon for chronic active hepatitis B.
Authors: M G Anderson, T J Harrison, G Alexander, A J Zuckerman, I M Murray-Lyon
Journal: Gut (1987)

Thirty male patients (27 homosexual) with biopsy proven chronic active hepatitis B were randomised to receive lymphoblastoid interferon (Wellferon) or no treatment. All patients were HBeAg positive and had continuing viral replication. Patients receiving treatment were given a single daily intramuscular injection of interferon for 28 days at a starting dose of 2.5 MU/m2 increasing to a maximum of 7.5 MU/m2/day. Transient side effects of malaise and influenza like symptoms occurred in all patients and resolved rapidly after treatment. Hepatitis B viral replication was suppressed during interferon treatment in all patients but the effect was limited to the period of therapy. After one year there was no appreciable difference in viral markers between the two groups of patients and this treatment schedule appears less effective than the thrice weekly, three month regimes recently reported from other centres.
Factor V Leiden (Resistance to Activated Protein C) Increases the Risk of Myocardial Infarction in Young Women
Authors: F.R. Rosendaal, D.S. Siscovick, S.M. Schwartz, R.K. Beverly, B.M. Psaty, W.T. Longstreth, T.E. Raghunathan, T.D. Koepsell, P.H. Reitsma
Journal: Blood (1997)
Evidence for subcomplexes in the Fanconi anemia pathway
Authors: Annette L. Medhurst, El Houari Laghmani, Jurgen Steltenpool, Miriam Ferrer, Chantal Fontaine, Jan de Groot, Martin A. Rooimans, Rik J. Scheper, Amom Ruhikanta Meetei, Weidong Wang, Hans Joenje, Johan P. de Winter
Journal: Blood (2006)
The distribution of blood flow, oxygen consumption, and work output among the respiratory muscles during unobstructed hyperventilation.
Authors: C H Robertson, M A Pagel, R L Johnson
Journal: Journal of Clinical Investigation (1977)

An animal model was developed to describe respiratory muscle work output, blood flow, and oxygen consumption during mechanical ventilation, resting spontaneous ventilation, and the increased unobstructed ventilatory efforts induced by CO2 rebreathing. Almost all of the work of breathing was inspiratory work at all ventilatory levels; thus, only blood flows to the diaphragm and external intercostals increased in the transition from mechanical to spontaneous ventilation, and they further increased linearly as ventilatory work was incrementally augmented ninefold by CO2 rebreathing. No other muscles of inspiration manifest increased blood flows. A small amount of expiratory work was measured at high ventilatory volumes during which two expiratory muscles (transverse abdominal and intercostals) had moderate increases in blood flow. Blood pressure did not change, but cardiac output doubled. Arterial-venous oxygen content difference across the diaphragm increased progressively, so oxygen delivery was augmented by both increased blood flow and increased oxygen extraction at all work loads. Oxygen consumption increased linearly as work of breathing increased, so efficiency did not change significantly. The mean efficiency of the respiratory muscles was 15.5%. These results differ significantly from the patterns previously observed by us during increased work of breathing induced by inspiratory resistance, suggesting a different distribution of work load among the various muscles of respiration, a different fractionation of oxygen delivery between blood flow and oxygen extraction, and a higher efficiency when shortening, not tension development, of the muscle is increased.
Necrotizing herpes zoster mimicking relapse of vasculitis in angioimmunoblastic lymphadenopathy with dysproteinaemia
Authors: R. BONI, R. DUMMER, C. DOMMANN-SCHERRER, S. DOMMANN, O.R. ZIMMERMANN, H. JOLLER-JEMELKA, G. BURG
Journal: British Journal of Dermatology (1995)

An 81‐year‐old man presented with a generalized maculopapular rush, lymphadenopathy, conjunctivitis and arthritis. Vasculitis was confirmed by skin biopsy and by direct immunofluorescence, which showed perivascular C3 and granular IgM accumulauon. Histology of an inguinal lymph node was diagnostic for angioimmunoblastic lymphadenopalhy with dysproteinaemia (AILD), and this was confirmed by the finding of hypergammaglobulinaemia and elevated IgE levels. Immuno‐histology on a lymph node biopsy showcd a T‐helper cell (CD4) intiltrale expressing the intcrleukin (ILJ‐2 receptor alpha and beta chains. While recciving prednisone 100mg/day, the patient developed new lesions. mimicking a relapse of vasculitis, which were subsequently shown to be necrotizing herpes zoster. Serum IL‐2 and IL‐6 levels were elevated. To our knowledge, this is the tirsl report of simultaneouselevation of IL‐2 and IL‐6 in AILD: IL‐2 may be involved in proliferation of the malignant cell clone. and IL‐6 in the pathogenesis of both the vasculitis (via endothelial cell activations and the hypergammaglobulinaemia.
Effect of Everolimus on Bone Marker Levels and Progressive Disease in Bone in BOLERO-2
Authors: Michael Gnant, Jose Baselga, Hope S. Rugo, Shinzaburo Noguchi, Howard A. Burris, Martine Piccart, Gabriel N. Hortobagyi, Janice Eakle, Hirofumi Mukai, Hiroji Iwata, Matthias Geberth, Lowell L. Hart, Peyman Hadji, Mona El-Hashimy, Shantha Rao, Tetiana Taran, Tarek Sahmoud, David Lebwohl, Mario Campone, Kathleen I. Pritchard
Journal: JNCI Journal of the National Cancer Institute (2013)

BackgroundBreast Cancer Trials of Oral Everolimus 2 (BOLERO-2), a phase III study in postmenopausal women with estrogen receptor–positive breast cancer progressing despite nonsteroidal aromatase inhibitor therapy, showed statistically significant benefits with adding everolimus to exemestane. Moreover, in preclinical studies, mammalian target of rapamycin inhibition was associated with decreased osteoclast survival and activity. Exploratory analyses in BOLERO-2 evaluated the effect of everolimus on bone marker levels and progressive disease in bone.