tbuckley/cabot-search huggingface dataset:
Long-Term Safety and Efficacy of Drug-Eluting versus Bare-Metal Stents in Sweden
Authors: Stefan K. James, Ulf Stenestrand, Johan Lindbäck, Jörg Carlsson, Fredrik Scherstén, Tage Nilsson, Lars Wallentin, Bo Lagerqvist
Journal: New England Journal of Medicine (2009)

The long-term safety and efficacy of drug-eluting coronary stents have been questioned.We evaluated 47,967 patients in Sweden who received a coronary stent and were entered into the Swedish Coronary Angiography and Angioplasty Registry between 2003 and 2006 and for whom complete follow-up data were available for 1 to 5 years (mean, 2.7). In the primary analysis, we compared patients who received one drug-eluting coronary stent (10,294 patients) with those who received one bare-metal stent (18,659), after adjustment for differences in clinical characteristics of the patients and characteristics of the vessels and lesions.Analyses of outcome were based on 2380 deaths and 3198 myocardial infarctions. There was no overall difference between the group that received drug-eluting stents and the group that received bare-metal stents in the combined end point of death or myocardial infarction (relative risk with drug-eluting stents, 0.96; 95% confidence interval [CI], 0.89 to 1.03) or the individual end points of death (relative risk, 0.94; 95% CI, 0.85 to 1.05) and myocardial infarction (relative risk, 0.97; 95% CI, 0.88 to 1.06), and there was no significant difference in outcome among subgroups stratified according to the indication for stent implantation. Patients who received drug-eluting stents in 2003 had a significantly higher rate of late events than patients who received bare-metal stents in the same year, but we did not observe any difference in outcome among patients treated in later years. The average rate of restenosis during the first year was 3.0 events per 100 patient-years with drug-eluting stents versus 4.7 with bare-metal stents (adjusted relative risk, 0.43; 95% CI, 0.36 to 0.52); 39 patients would need to be treated with drug-eluting stents to prevent one case of restenosis. Among high-risk patients, the adjusted risk of restenosis was 74% lower with drug-eluting stents than with bare-metal stents, and only 10 lesions would need to be treated to prevent one case of restenosis.As compared with bare-metal stents, drug-eluting stents are associated with a similar long-term incidence of death or myocardial infarction and provide a clinically important decrease in the rate of restenosis among high-risk patients.
Disruption of Protein Arginine <i>N</i> -Methyltransferase 2 Regulates Leptin Signaling and Produces Leanness In Vivo Through Loss of STAT3 Methylation
Authors: Hiroaki Iwasaki, Jason C. Kovacic, Michelle Olive, Jeanette K. Beers, Takanobu Yoshimoto, Martin F. Crook, Leonardo H. Tonelli, Elizabeth G. Nabel
Journal: Circulation Research (2010)

Rationale: Arginine methylation by protein N -arginine methyltransferases (PRMTs) is an important posttranslational modification in the regulation of protein signaling. PRMT2 contains a highly conserved catalytic Ado-Met binding domain, but the enzymatic function of PRMT2 with respect to methylation is unknown. The JAK-STAT pathway is proposed to be regulated through direct arginine methylation of STAT transcription factors, and STAT3 signaling is known to be required for leptin regulation of energy balance. Objective: To identify the potential role of STAT3 arginine methylation by PRMT2 in the regulation of leptin signaling and energy homeostasis. Methods and Results: We identified that PRMT2 −/− mice are hypophagic, lean, and have significantly reduced serum leptin levels. This lean phenotype is accompanied by resistance to food-dependent obesity and an increased sensitivity to exogenous leptin administration. PRMT2 colocalizes with STAT3 in hypothalamic nuclei, where it binds and methylates STAT3 through its Ado-Met binding domain. In vitro studies further clarified that the Ado-Met binding domain of PRMT2 induces STAT3 methylation at the Arg31 residue. Absence of PRMT2 results in decreased methylation and prolonged tyrosine phosphorylation of hypothalamic STAT3, which was associated with increased expression of hypothalamic proopiomelanocortin following leptin stimulation. Conclusions: These data elucidate a molecular pathway that directly links arginine methylation of STAT3 by PRMT2 to the regulation of leptin signaling, suggesting a potential role for PRMT2 antagonism in the treatment of obesity and obesity-related syndromes.
Mechanisms of Immune Lysis of the Red Cells in Hereditary Erythroblastic Multinuclearity with a Positive Acidified Serum Test and Paroxysmal Nocturnal Hemoglobinuria
Authors: Wendell F. Rosse, Gerald L. Logue, Judith Adams, John H. Crookston
Journal: Journal of Clinical Investigation (1974)

The red cells of patients with hereditary erythroblastic multinuclearity with a positive acidified serum test (HEMPAS), a form of congenital dyserythropoietic anemia, and the cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) are lysed more readily than normal cells by certain antibodies, notably cold agglutinins (anti-I) and complement. With some but not other examples of anti-I, HEMPAS and PNH cells adsorbed more antibody than normal cells. Equal quantities of adsorbed antibody bound equal quantities of the first component of complement (C1) to normal, PNH, and HEMPAS cells. However, for a given quantity of bound antibody and C1, much more of the fourth component of complement (C4) was bound to HEMPAS cells than to normal cells. This resulted in the binding of proportionately larger quantities of the third component of complement (C3) to these cells. The same amount of bound C3 was found on the membranes of normal and HEMPAS cells for a given degree of lysis. Hence, the marked increase in lysis of HEMPAS cells is due to the increased adsorption of antibody and/or increased binding of C4.PNH cells bound the same amount of C4 per bound C1 as normal cells but bound more C3 than normal cells. However, the mean concentration of C3 on the membrane of PNH cells was one-third to one-fifth that on normal cells for a given degree of lysis. Hence, the increased lysis of PNH cells is due to the increased binding of C3 and increased hemolytic effectiveness of the bound C3.
Apolipoprotein E polymorphism in Vietnamese children and its relationship to plasma lipid and lipoprotein levels
Authors: Nghiem Nguyet Thu, Ta Thi Tuyet Mai, Reiko Ohmori, Masatoshi Kuroki, Nguyen Van Chuyen, Nguyen Thi Kim Hung, Masanobu Kawakami, Kazuo Kondo
Journal: Metabolism (2004)
Targeting gut flora to prevent progression of hepatocellular carcinoma
Authors: Marion Darnaud, Jamila Faivre, Nicolas Moniaux
Journal: Journal of Hepatology (2012)

Increased translocation of intestinal bacteria is a hallmark of chronic liver disease and contributes to hepatic inflammation and fibrosis. Here we tested the hypothesis that the intestinal microbiota and Toll-like receptors (TLRs) promote hepatocellular carcinoma(HCC), a long-term consequence of chronic liver injury, inflammation,and fibrosis. Hepatocarcinogenesis in chronically injured livers depended on the intestinal microbiota and TLR4 activation in nonbone-marrow-derived resident liver cells. TLR4 and the intestinal microbiota were not required for HCC initiation but for HCC promotion, mediating increased proliferation, expression of the hepatomitogen epiregulin, and prevention of apoptosis. Gut sterilization restricted to late stages of hepatocarcinogenesis reduced HCC, suggesting that the intestinal microbiota and TLR4 represent therapeutic targets for HCC prevention in advanced liver disease.
Quantum proteolysis by neutrophils: implications for pulmonary emphysema in α1-antitrypsin deficiency
Authors: Edward J. Campbell, Melody A. Campbell, Steve S. Boukedes, Caroline A. Owen
Journal: Journal of Clinical Investigation (1999)

Traditional enzyme kinetics provide a poor explanation for the increased risk of lung injury in α1-antitrypsin (AAT) deficiency. Millimolar concentrations of leukocyte elastase, when released from single azurophil granules of activated neutrophils, lead to evanescent quantum bursts of proteolytic activity before catalysis is quenched by pericellular inhibitors. Herein, we tested the possibility that quantum proteolytic events are abnormal in AAT deficiency. We incubated neutrophils on opsonized fluoresceinated fibronectin in serum from individuals with various AAT phenotypes, and then measured and modeled quantum proteolytic events. The mean areas of the events in serum from heterozygous individuals (Pi MZ and Pi SZ) were slightly, but significantly, larger than those in serum from normal patients (Pi M). In marked contrast, mean areas of events in serum from AAT-deficient individuals were 10-fold larger than those in serum from normal patients. Diffusion modeling predicted that local elastase concentrations exceed AAT concentrations for less than 20 milliseconds and for more than 80 milliseconds in Pi M and Pi Z individuals, respectively. Thus, quantum proteolytic events are abnormally large and prolonged in AAT deficiency, leading directly to an increased risk of tissue injury in the immediate vicinity of activated neutrophils. These results have potentially important implications for the pathogenesis and prevention of lung disease in AAT deficiency.
A microRNA panel to discriminate carcinomas from high-grade intraepithelial neoplasms in colonoscopy biopsy tissue
Authors: Shuyang Wang, Lei Wang, Nayima Bayaxi, Jian Li, Wim Verhaegh, Angel Janevski, Vinay Varadan, Yiping Ren, Dennis Merkle, Xianxin Meng, Xue Gao, Huijun Wang, Jiaqiang Ren, Winston Patrick Kuo, Nevenka Dimitrova, Ying Wu, Hongguang Zhu
Journal: Gut (2012)

<h3>Objective</h3> It is a challenge to differentiate invasive carcinomas from high-grade intraepithelial neoplasms in colonoscopy biopsy tissues. In this study, microRNA profiles were evaluated in the transformation of colorectal carcinogenesis to discover new molecular markers for identifying a carcinoma in colonoscopy biopsy tissues where the presence of stromal invasion cells is not detectable by microscopic analysis. <h3>Methods</h3> The expression of 723 human microRNAs was measured in laser capture microdissected epithelial tumours from 133 snap-frozen surgical colorectal specimens. Three well-known classification algorithms were used to derive candidate biomarkers for discriminating carcinomas from adenomas. Quantitative reverse-transcriptase PCR was then used to validate the candidates in an independent cohort of macrodissected formalin-fixed paraffin-embedded colorectal tissue samples from 91 surgical resections. The biomarkers were applied to differentiate carcinomas from high-grade intraepithelial neoplasms in 58 colonoscopy biopsy tissue samples with stromal invasion cells undetectable by microscopy. <h3>Results</h3> One classifier of 14 microRNAs was identified with a prediction accuracy of 94.1% for discriminating carcinomas from adenomas. In formalin-fixed paraffin-embedded surgical tissue samples, a combination of miR-375, miR-424 and miR-92a yielded an accuracy of 94% (AUC=0.968) in discriminating carcinomas from adenomas. This combination has been applied to differentiate carcinomas from high-grade intraepithelial neoplasms in colonoscopy biopsy tissues with an accuracy of 89% (AUC=0.918). <h3>Conclusions</h3> This study has found a microRNA panel that accurately discriminates carcinomas from high-grade intraepithelial neoplasms in colonoscopy biopsy tissues. This microRNA panel has considerable clinical value in the early diagnosis and optimal surgical decision-making of colorectal cancer.
Abnormal Pressor Response to Vasopressin in Patients With Cirrhosis: Evidence for Impaired Buffering Mechanisms
Authors: Richard Moreau, Antoine Hadengue, Thierry Soupison, Guy Mechin, Michel Assous, Jacqueline Roche-Sicot, Christian Sicot
Journal: Hepatology (1990)

In patients with cirrhosis, vasopressin infusion induces sustained vasoconstriction and elevation of arterial pressure. The vasopressor effect could be caused by impairment of mechanisms normally aimed at buffering increases in arterial pressure (reflex bradycardia and decreases in arteriolar resistance). We studied the acute effects of continuous vasopressin infusion (0.4 IU/min) on systemic hemodynamics in seven patients with cirrhosis and in six patients without cirrhosis (controls). Vasopressin effects on systemic O 2 consumption were also studied. In both groups, vasopressin infusion induced similar peak increases in arterial pressure, followed by similar decreases in heart rate and cardiac output. However, cirrhotic patients and controls differed 30 min after the start of vasopressin infusion. At 30 min, mean arterial pressure, diastolic arterial pressure and systemic vascular resistance remained significantly higher than preinfusion values in patients with cirrhosis. No decrease in systemic O 2 consumption occurred in cirrhotic patients. In controls, at 30 min, mean arterial pressure and diastolic arterial pressure had returned to baseline. Systemic vascular resistance was not significantly higher than the preinfusion value and systemic O 2 consumption had significantly decreased to below preinfusion values. We conclude that the vasopressor effect of vasopressin is abnormally sustained in patients with cirrhosis. This might be caused by insufficient buffering of vasopressin–induced arteriolar constriction rather than by abnormal vagal control of heart rate. In turn, as suggested by the lack of a decrease in systemic O 2 consumption, persistent arteriolar constriction might be related to abnormally sustained sympathetic vascular tone in patients with cirrhosis. (Hepatology 1990;12:7-12).
Aberrant ZNF423 impedes B cell differentiation and is linked to adverse outcome of <i>ETV6-RUNX1</i> negative B precursor acute lymphoblastic leukemia
Authors: Lena Harder, Georg Eschenburg, Antonia Zech, Neele Kriebitzsch, Benjamin Otto, Thomas Streichert, Anna-Sophie Behlich, Kevin Dierck, Bine Klingler, Arne Hansen, Martin Stanulla, Martin Zimmermann, Elisabeth Kremmer, Carol Stocking, Martin A. Horstmann
Journal: The Journal of Experimental Medicine (2013)

Differentiation arrest is a hallmark of acute leukemia. Genomic alterations in B cell differentiation factors such as PAX5, IKZF1, and EBF-1 have been identified in more than half of all cases of childhood B precursor acute lymphoblastic leukemia (ALL). Here, we describe a perturbed epigenetic and transcriptional regulation of ZNF423 in ALL as a novel mechanism interfering with B cell differentiation. Hypomethylation of ZNF423 regulatory sequences and BMP2 signaling result in transactivation of ZNF423α and a novel ZNF423β-isoform encoding a nucleosome remodeling and histone deacetylase complex–interacting domain. Aberrant ZNF423 inhibits the transactivation of EBF-1 target genes and leads to B cell maturation arrest in vivo. Importantly, ZNF423 expression is associated with poor outcome of ETV6-RUNX1–negative B precursor ALL patients. Our work demonstrates that ALL is more than a genetic disease and that epigenetics may uncover novel mechanisms of disease with prognostic implications.
Understanding and Managing Zoonotic Risk in the New Livestock Industries
Authors: Marco Liverani, Jeff Waage, Tony Barnett, Dirk U. Pfeiffer, Jonathan Rushton, James W. Rudge, Michael E. Loevinsohn, Ian Scoones, Richard D. Smith, Ben S. Cooper, Lisa J. White, Shan Goh, Peter Horby, Brendan Wren, Ozan Gundogdu, Abigail Woods, Richard J. Coker
Journal: Environmental Health Perspectives (2013)

In many parts of the world, livestock production is undergoing a process of rapid intensification. The health implications of this development are uncertain. Intensification creates cheaper products, allowing more people to access animal-based foods. However, some practices associated with intensification may contribute to zoonotic disease emergence and spread: for example, the sustained use of antibiotics, concentration of animals in confined units, and long distances and frequent movement of livestock.Here we present the diverse range of ecological, biological, and socioeconomic factors likely to enhance or reduce zoonotic risk, and identify ways in which a comprehensive risk analysis may be conducted by using an interdisciplinary approach. We also offer a conceptual framework to guide systematic research on this problem.We recommend that interdisciplinary work on zoonotic risk should take into account the complexity of risk environments, rather than limiting studies to simple linear causal relations between risk drivers and disease emergence and/or spread. In addition, interdisciplinary integration is needed at different levels of analysis, from the study of risk environments to the identification of policy options for risk management.Given rapid changes in livestock production systems and their potential health implications at the local and global level, the problem we analyze here is of great importance for environmental health and development. Although we offer a systematic interdisciplinary approach to understand and address these implications, we recognize that further research is needed to clarify methodological and practical questions arising from the integration of the natural and social sciences.
Azithromycin concentrations at the sites of pulmonary infection
Authors: DR Baldwin, R Wise, JM Andrews, JP Ashby, D Honeybourne
Journal: European Respiratory Journal (1990)

Azithromycin is a new macrolide antimicrobial. The distribution to the potential sites of pulmonary infection was assessed after the administration of a single 500 mg oral dose to 22 patients undergoing fibreoptic bronchoscopy. Concentrations of azithromycin in sputum, bronchial mucosa, eptihelial lining fluid (ELF) and alveolar macrophages (AM) were determined at intervals up to 96 h after dosing. The mean serum concentration was low at 12 h (0.13 micrograms.ml-1, SEM 0.05) but was still detectable at 96 h (0.01 micrograms.ml-1). In contrast, peak sputum ELF, bronchial mucosal and AM levels were found at 48 h. Bronchial mucosal concentrations were significantly greater than ELF concentrations, which were in turn greater than sputum concentrations. Mean peak AM concentrations were sixfold greater than bronchial mucosal concentrations (23 micrograms.ml-1, SEM 5.1 and 3.89 micrograms.ml-1, SEM 1.2, respectively). The high intracellular concentrations indicate that azithromycin is likely to be effective for sensitive intracellular pathogens and the favourable penetration into sputum, ELF and bronchial mucosa suggest that it should be useful in pneumonia and bronchial infections.
CD8 T-cell Responses against Cyclin B1 in Breast Cancer Patients with Tumors Overexpressing p53
Authors: Rikke Bæk Sørensen, Rikke Sick Andersen, Inge Marie Svane, Lotte Engell-Noerregaard, Sine R. Hadrup, Eva Balslev, Mads Hald Andersen, Per thor Straten
Journal: Clinical Cancer Research (2009)

This study aimed to examine CD8 T-cell reactivity in breast cancer patients against cyclin B1-derived peptides restricted by the human leukocyte antigen (HLA)-A2 molecule.Peripheral blood mononuclear cells from 36 breast cancer patients were analyzed by enzyme-linked immunosorbent spot (ELISPOT) for the presence of T cells recognizing the cyclin B1-derived peptides CB9 (AKYLMELTM) and CB-P4 (AKYLMELCC), in addition to modified versions of CB9, CB9L2 (ALYLMELTM) and CB9M2 (AMYLMELTM), both of which display higher affinity to HLA-A2.Twelve patients harbored a memory CD8 T-cell response against at least one of the peptides; strongest reactivity was detected against the CB9L2 peptide. Because the level of cyclin B1 has been shown to be influenced by the level of p53, which in turn is elevated in cancer cells because of point mutation, we analyzed the level of p53 protein in biopsies from the patients by immune histochemistry. Combined data showed that anti-cyclin B1 reactivity was predominantly detected in patients with tumors characterized by elevated expression of p53. Interestingly, no reactivity was detected against six peptides derived from the p53 protein.Our data support the notion of cyclin B1 as a prominent target for immunologic recognition in cancer patients harboring p53-mutated cancer cells. Because mutation of p53 is one of the most frequent genetic alterations in human cancers, this suggests that immunotherapy based on targeting of cyclin B1 is broadly applicable in a large proportion of cancer patients.
Antigenic Fingerprinting of H5N1 Avian Influenza Using Convalescent Sera and Monoclonal Antibodies Reveals Potential Vaccine and Diagnostic Targets
Authors: Surender Khurana, Amorsolo L. Suguitan, Yonaira Rivera, Cameron P. Simmons, Antonio Lanzavecchia, Federica Sallusto, Jody Manischewitz, Lisa R. King, Kanta Subbarao, Hana Golding
Journal: PLoS Medicine (2009)

Using whole-genome-fragment phage display libraries, Hana Golding and colleagues identify the viral epitopes recognized by serum antibodies in humans who have recovered from infection with H5N1 avian influenza.
The American Psychiatric Publishing Textbook of Mood Disordersedited by Dan J. Stein, M.D., Ph.D., David J. Kupfer, M.D., and Alan F. Schatzberg, M.D. Arlington, Va., American Psychiatric Publishing, 2006, 792 pp. $119.00.
Authors: VICTOR I. REUS
Journal: American Journal of Psychiatry (2006)
<i>CRKL</i> as a Lung Cancer Oncogene and Mediator of Acquired Resistance to EGFR Inhibitors: Is It All That It Is Cracked Up to Be?
Authors: Marc Ladanyi
Journal: Cancer Discovery (2011)

Cheung and colleagues demonstrate that amplified CRKL can function as a driver oncogene in lung adenocarcinoma, activating both RAS and RAP1 to induce mitogen-activated protein kinase signaling. In addition, they show that CRKL amplification may be another mechanism for primary or acquired resistance to epidermal growth factor receptor kinase inhibitors.
COMPLICATIONS OF LAPAROSCOPIC CHOLECYSTECTOMY
Authors: Daniel B. Jones, M.D, Nathaniel J. Soper, M.D. F.A.C.S
Journal: Annual Review of Medicine (1996)

▪ Abstract Video technology allows surgeons to offer patients operations through small incisions. While these minimally invasive techniques have been employed for a wide range of operations for many years, only recently has a laparoscopic cholecystectomy been possible. Compared to the same operation performed via laparotomy, it is deemed the “gold standard.” Overall mortality after laparoscopic cholecystectomy ranges from 0–1%, and the rate of major complications is less than 5%. As a group, general surgeons are beyond their initial learning curve for laparoscopic cholecystectomy, but the majority of iatrogenic injuries can be successfully avoided by appreciating the limitations and pitfalls of laparoscopic surgery, and by carefully dissecting the hepatocystic triangle before dividing any structure. Early identification and management of complications will minimize potentially devastating complications of small, unrecognized injuries. Physicians need to accurately advise patients of the proposed advantages and potential problems of laparoscopic cholecystectomy before referring them to a surgeon.