tbuckley/cabot-search huggingface dataset:
S105 Innate B1 cells are a novel source of IL-17 in chronic pulmonary Pseudomonas aeruginosa infection
Authors: HK Bayes, T Evans
Journal: Thorax (2013)

<h3>Introduction and Objectives</h3> <i>Pseudomonas aeruginosa</i> (PA) is an important respiratory pathogen resulting in damaging neutrophilic responses. The cytokine IL-17 is important in orchestrating such inflammation. Cells producing IL-17, such as Th17 cells, have been shown to be important in host defense in chronic pulmonary PA infection. We set out to determine the origin and role of IL-17 in a model of chronic pulmonary PA infection. <h3>Methods</h3> Experimental chronic pulmonary infection in mice was produced by intra-tracheal instillation of mucoid PA strains embedded in agar-beads; sterile beads were utilised as controls. Thoracic lymph nodes (LNs), splenocytes and peritoneal B1a cells were restimulated with PA followed by cytokine assay and immunostaining to define responding cell subsets. PA-specific immunoglobulins were measured in sera and culture supernatants. Intrapulmonary B cells were identified via immunohistochemistry. Mice genetically engineered to lack B cells (µMT strain) were utilised to examine the effect on pathogenesis in the absence of B cell responses. <h3>Results</h3> Chronic PA infection developed in 43% (SD: 25%) of infected animals at 14-days. Following infection, the pulmonary LN B cell compartment expanded, with a large B1 population (B220<sup>+</sup> CD19<sup>+</sup> CD43<sup>+</sup> IgM hi IgD lo and predominantly CD5<sup>+</sup> ) that expressed intracellular IL-17A. Infected animals also developed peribronchial B220<sup>+</sup> cellular foci. In mediastinal LNs following infection, PA-specific responses were dominated by B220<sup>+</sup> CD19<sup>+</sup> CD43<sup>+</sup> CD23<sup>-</sup>B5<sup>+</sup> cells expressing and producing IL-17A and IL-22 as well as PA-specific IgM but not IgG. This PA-specific B1 response was not seen in the thoracic lymph nodes of sterile-bead treated animals. In splenocytes, there was a pre-existing B cell response to PA with identical features. Peritoneal B1a cells isolated from untreated controls also produced IL-17A, IL-22 and anti-PA IgM following infection, confirming the existence of pre-existing B1 cells that can respond to PA. In µMT animals, chronic colonisation rates, bacterial burden and neutrophilic inflammation did not differ from WT littermates. However, classical PA-specific Th17 responses dominated following infection in µMT animals, suggesting alternative compensatory IL-17 sources acting in the absence of B cells. <h3>Conclusions</h3> In chronic pulmonary PA infection, innate-like B1 cells migrate to the site of infection and are a novel source of pro-inflammatory IL-17 cytokines.
Improving the Quality of Care for Medicare Patients With Acute Myocardial Infarction
Authors: Thomas A. Marciniak, Edward F. Ellerbeck, Martha J. Radford, Timothy F. Kresowik, Jay A. Gold, Harlan M. Krumholz, Catarina I. Kiefe, Richard M. Allman, Robert A. Vogel, Stephen F. Jencks
Journal: JAMA (1998)

Context.—Medicare has a legislative mandate for quality assurance, but the effectiveness of its population-based quality improvement programs has been difficult to establish.Objective.—To improve the quality of care for Medicare patients with acute myocardial infarction.Design.—Quality improvement project with baseline measurement, feedback, remeasurement, and comparison samples.Setting.—All acute care hospitals in the United States.Patients.—Preintervention and postintervention samples included all Medicare patients in Alabama, Connecticut, Iowa, and Wisconsin discharged with principal diagnoses of acute myocardial infarctions during 2 periods, June 1992 through December 1992 and August 1995 through November 1995. Indicator comparisons were made with a random sample of Medicare patients in the rest of the nation discharged with acute myocardial infarctions from August 1995 through November 1995. Mortality comparisons involved all Medicare patients nationwide with inpatient claims for acute myocardial infarctions during 2 periods, June 1992 through May 1993 and August 1995 through July 1996.Intervention.—Data feedback by peer review organizations.Main Outcome Measures.—Quality indicators derived from clinical practice guidelines, length of stay, and mortality.Results.—Performance on all quality indicators improved significantly in the 4 pilot states. Administration of aspirin during hospitalization in patients without contraindications improved from 84% to 90% (P<.001), and prescription of β-blockers at discharge improved from 47% to 68% (P<.001). Mortality at 30 days decreased from 18.9% to 17.1% (P=.005) and at 1 year from 32.3% to 29.6% (P<.001). These improvements in quality occurred during a period when median length of stay decreased from 8 days to 6 days. Performance on all quality indicators except reperfusion was better in the pilot states than in the rest of the nation in 1995, and the differences were statistically significant for aspirin use at discharge (P<.001), β-blocker use (P<.001), and smoking cessation counseling (P=.02). Postinfarction mortality was not significantly different between the pilot states and the rest of the nation during the baseline period, although it was slightly but significantly better in the pilot states during the follow-up period (absolute mortality difference at 1 year, 0.9%; P=.004).Conclusions.—The quality of care for Medicare patients with acute myocardial infarction has improved in the Cooperative Cardiovascular Project pilot states. Performance on the defined quality indicators appeared to be better in the pilot states than in the rest of the nation in 1995 and was associated with reduced mortality.
Comparative analysis of minimal residual disease detection using four-color flow cytometry, consensus IgH-PCR, and quantitative IgH PCR in CLL after allogeneic and autologous stem cell transplantation
Authors: S Böttcher, M Ritgen, C Pott, M Brüggemann, T Raff, S Stilgenbauer, H Döhner, P Dreger, M Kneba
Journal: Leukemia (2004)
Oncolytic Viral Therapy for Prostate Cancer: Efficacy of Reovirus as a Biological Therapeutic
Authors: Chandini M. Thirukkumaran, Michael J. Nodwell, Kensuke Hirasawa, Zhong-Qiao Shi, Roman Diaz, Joanne Luider, Randal N. Johnston, Peter A. Forsyth, Anthony M. Magliocco, Patrick Lee, Sandra Nishikawa, Bryan Donnelly, Matt Coffey, Kiril Trpkov, Kevin Fonseca, Jason Spurrell, Don G. Morris
Journal: Cancer Research (2010)

Reovirus is a nonattenuated double-stranded RNA virus that exploits aberrant signaling pathways allowing selective cytotoxicity against multiple cancer histologies. The use of reovirus as a potential treatment modality for prostate cancer has not previously been described, and in this study evidence of in vitro and in vivo activity against prostate cancer was seen both in preclinical models and in six patients. The human prostate carcinoma cell lines PC-3, LN-CaP, and DU-145 exposed to replication-competent reovirus showed evidence of infection as illustrated by viral protein synthesis, cytopathic effect, and release of viral progeny. This oncolytic effect was found to be manifested through apoptosis, as DNA fragmentation, Apo 2.7 expression, Annexin V binding, and poly(ADP-ribose) polymerase cleavage were observed in live reovirus-infected cells, but not in uninfected or dead virus-treated cells. In vivo, hind flank severe combined immunodeficient/nonobese diabetic murine xenograft showed reduction in tumor size when treated with even a single intratumoral injection of reovirus. Finally, intralesional reovirus injections into a cohort of six patients with clinically organ-confined prostate cancer resulted in minimal side effects and evidence of antitumor activity. Histologic analysis after prostatectomy found a significant CD8 T-cell infiltration within the reovirus-injected areas as well as evidence of increased caspase-3 activity. These findings suggest that reovirus therapy may provide a promising novel treatment for prostate cancer and also imply a possible role for viral immune targeting of tumor.
Validation of a simple risk stratification tool for patients implanted with Cardiac Resynchronization Therapy: the <scp>VALID‐CRT</scp> risk score
Authors: Maurizio Gasparini, Catherine Klersy, Cristophe Leclercq, Maurizio Lunati, Maurizio Landolina, Angelo Auricchio, Massimo Santini, Giuseppe Boriani, Alessandro Proclemer, Francisco Leyva
Journal: European Journal of Heart Failure (2015)
Heparanase Expression at the Invasion Front of Human Head and Neck Cancers and Correlation with Poor Prognosis
Authors: Philipp Beckhove, Burkhard M. Helmke, Yvonne Ziouta, Mariana Bucur, Wolfgang Dörner, Carolin Mogler, Gerhard Dyckhoff, Christel Herold-Mende
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Head and neck squamous cell carcinomas (HNSCC) are characterized by a poor prognosis due to aggressive, recurrent tumor growth. Expression of the extracellular matrix–degrading enzyme heparanase was associated with poorer prognosis in several cancers. We analyzed the presence of heparanase in HNSCC tissues and tumor cells and its potential prognostic significance. Experimental Design: We analyzed the expression of the active form of heparanase in HNSCC tissues in corresponding tumor cell cultures and after xenotransplantation of tumor cell cultures into NOD/Scid mice by immunohistochemistry, Western blot analysis, and reverse transcription-PCR in altogether 25 patients and did a comparison with clinicopathologic data of the patients. Results: Heparanase expression in situ was detected in all tumor biopsies in the tumor stroma and in tumor cells from 13 of 19 primary tumors and 9 of 12 lymph node metastases. Heparanase was localized in disseminated tumor cells, in tumor cell clusters invading adjacent stromal tissues, and in tumor cells at the tumor invasion front. Lymph node metastases expressed higher levels of heparanase compared with corresponding primary tumors. In contrast to a heterogeneous expression pattern in tumor tissues, all corresponding HNSCC tumor cell cultures showed a rather homogeneous heparanase expression on the mRNA and protein levels. Comparison of heparanase expression in situ and in corresponding tumor cell cultures in vitro or after xenotransplantation into NOD/Scid mice revealed that heparanase expression was regulated in vivo. Lack of heparanase in tumor cells from primary tumors or lymph node metastases was correlated with prolonged disease-free survival and overall survival. Conclusion: Heparanase expression seems to be involved in the invasiveness and aggressiveness of HNSCC.
The Cell Fate Determination Factor DACH1 Is Expressed in Estrogen Receptor-α–Positive Breast Cancer and Represses Estrogen Receptor-α Signaling
Authors: Vladimir M. Popov, Jie Zhou, L. Andrew Shirley, Judy Quong, Wen-Shuz Yeow, Jennifer A. Wright, Kongming Wu, Hallgeir Rui, Ratna K. Vadlamudi, Jie Jiang, Rakesh Kumar, Chenguang Wang, Richard G. Pestell
Journal: Cancer Research (2009)

The Dachshund (dac) gene, initially cloned as a dominant inhibitor of the Drosophila hyperactive EGFR mutant ellipse, encodes a key component of the cell fate determination pathway involved in Drosophila eye development. Analysis of more than 2,200 breast cancer samples showed improved survival by some 40 months in patients whose tumors expressed DACH1. Herein, DACH1 and estrogen receptor-alpha (ERalpha) expressions were inversely correlated in human breast cancer. DACH1 bound and inhibited ERalpha function. Nuclear DACH1 expression inhibited estradiol (E(2))-induced DNA synthesis and cellular proliferation. DACH1 bound ERalpha in immunoprecipitation-Western blotting, associated with ERalpha in chromatin immunoprecipitation, and inhibited ERalpha transcriptional activity, requiring a conserved DS domain. Proteomic analysis identified proline, glutamic acid, and leucine rich protein 1 (PELP1) as a DACH1-binding protein. The DACH1 COOH terminus was required for binding to PELP1. DACH1 inhibited induction of ERalpha signaling. E(2) recruited ERalpha and disengaged corepressors from DACH1 at an endogenous ER response element, allowing PELP1 to serve as an ERalpha coactivator. DACH1 expression, which is lost in poor prognosis human breast cancer, functions as an endogenous inhibitor of ERalpha function.
Osteoarthritis of the knee joint: an eight year prospective study.
Authors: L Massardo, I Watt, J Cushnaghan, P Dieppe
Journal: Annals of the Rheumatic Diseases (1989)

Thirty one patients (25 women, six men, mean age 71.7 years) with established osteoarthritis (OA) of the knee were examined clinically and radiologically on two occasions, eight years apart. Four patients thought they had got better, two of whom had striking functional improvement. Seven remained the same and 20 patients got worse, two needing knee surgery and many developing severe disabilities. Most of the patients had a history of slow acquisition of OA at new joint sites, hand disease emerging as the commonest other site of involvement. Changes in symptoms, disability, and radiographs did not correlate. Three of the four patients who improved symptomatically lost range of motion at the knee and developed more severe changes on their radiographs. Chondrocalcinosis of the knee was seen in five patients, including two of those who improved.
Restenosis after placement of Palmaz-Schatz stents in native coronary arteries. Initial results of a multicenter experience.
Authors: S G Ellis, M Savage, D Fischman, D S Baim, M Leon, S Goldberg, J W Hirshfeld, M W Cleman, P S Teirstein, C Walker
Journal: Circulation (1992)

BACKGROUND Several metallic intracoronary stents are currently undergoing preliminary evaluation to ascertain potential benefit as means to reduce the 30-40% incidence of restenosis after balloon angioplasty. METHODS AND RESULTS To determine the incidence and correlates of restenosis after placement of Palmaz-Schatz stents in native coronary arteries in the first group of patients selected for this procedure, clinical and quantitative angiographic data from 206 consecutive patients (221 stenoses) with successful stent placement (diameter stenosis &lt; 50%) were analyzed. Six patients (2.9%) had thrombosis-mediated stent closure within 1 month after stent placement and were excluded from long-term angiographic follow-up. One hundred eighty-one (91%) of the remaining 200 patients had angiography at 5.8 +/- 2.1 months. Patients with and without follow-up did not differ in any baseline characteristic; in particular, history of restenosis at the site stented (73% versus 65%), placement of multiple overlapping stents (17% versus 20%), and mean poststent diameter stenosis (16 +/- 12% versus 14 +/- 12%). The overall incidence of restenosis (diameter stenosis &gt; or = 50% at follow-up) in this group at high risk for restenosis was 36% (95% confidence interval, 29-43%) on a per-stenosis basis. The incidence of restenosis when a single stent was placed was 30% (95% confidence interval, 23-37%). Risk was dependent upon a history of restenosis (present versus absent 36% versus 16%, p = 0.02) and upon whether or not a poststent stenosis &lt; or = 0% was achieved (6% versus 33%, p = 0.02). When multiple overlapping stents were placed, restenosis occurred at 64% of sites, and placement of multiple stents was discouraged during the later phases of this study as these results became apparent. CONCLUSIONS Although multiple stents appear to yield a poor long-term result, placement of single stents may offer a benefit compared with standard coronary angioplasty, particularly if an excellent angiographic result can be obtained in patients without prior restenosis. Further randomized trials in such patients are needed.
AHA Dietary Guidelines
Authors: Ronald M. Krauss, Robert H. Eckel, Barbara Howard, Lawrence J. Appel, Stephen R. Daniels, Richard J. Deckelbaum, John W. Erdman, Penny Kris-Etherton, Ira J. Goldberg, Theodore A. Kotchen, Alice H. Lichtenstein, William E. Mitch, Rebecca Mullis, Killian Robinson, Judith Wylie-Rosett, Sachiko St. Jeor, John Suttie, Diane L. Tribble, Terry L. Bazzarre
Journal: Circulation (2000)
983 INCIDENCE OF HEPATOCELLULAR CARCINOMA IN HCV MONOINFECTED AND HIV COINFECTED PATIENTS WHO RECEIVED ANTIVIRAL TREATMENT
Authors: C. Leal Valdivieso, B. Revollo Barriga, I. Serra Matamala, R.M. Morillas Cunill, M. Sala Llinas, H. Masnou Ridaura, A. Bargalló Garcia, C. Tural Llàcher, R. Planas Vilà
Journal: Journal of Hepatology (2011)
Regulation of Sarcolemmal Na <sup>+</sup> /H <sup>+</sup> Exchanger Activity by Angiotensin II in Adult Rat Ventricular Myocytes
Authors: Suba Gunasegaram, Robert S. Haworth, David J. Hearse, Metin Avkiran
Journal: Circulation Research (1999)

Increased sarcolemmal Na(+)/H(+) exchanger activity has been implicated as a mediator of the cardiac actions of angiotensin II. We studied the receptor subtypes and signaling pathways involved in the regulation of sarcolemmal Na(+)/H(+) exchanger activity by angiotensin II in adult rat ventricular myocytes. Cells were loaded with the pH-sensitive fluoroprobe carboxy-seminaphthorhodafluor-1, and acid efflux rates estimated during recovery from intracellular acidosis were used to quantify exchanger activity. Sarcolemmal Na(+)/H(+) exchanger activity was not affected by angiotensin II alone but was increased by angiotensin II plus PD123319 (AT(2) antagonist). In contrast, angiotensin II plus losartan (AT(1) antagonist) or CGP42112A (AT(2) agonist) did not affect exchanger activity. The increase in Na(+)/H(+) exchanger activity induced by angiotensin II plus PD123319 was blocked by losartan, PD98059 (extracellular signal-regulated kinase inhibitor), GF109203X (protein kinase C inhibitor), and tyrphostin AG1478 (epidermal growth factor receptor kinase inhibitor). Extracellular signal-regulated kinase phosphorylation and activity, measured by immunoblot analysis and an immune-complex kinase assay, respectively, were increased significantly by angiotensin II plus PD123319; these increases were blocked by losartan and PD98059. The increase in extracellular signal-regulated kinase phosphorylation induced by angiotensin II plus PD123319 was blocked also by GF109203X and tyrphostin AG1478. These data show that AT(1) stimulation increases sarcolemmal Na(+)/H(+) exchanger activity in adult rat ventricular myocytes and that this response requires extracellular signal-regulated kinase activation through a protein kinase C- and epidermal growth factor receptor-mediated mechanism. The positive effect of AT(1) stimulation on Na(+)/H(+) exchanger activity is counteracted by simultaneous AT(2) stimulation through a mechanism that does not involve direct inhibition of the exchanger or attenuation of extracellular signal-regulated kinase activation.
Integrating diverse genomic data using gene sets
Authors: Svitlana Tyekucheva, Luigi Marchionni, Rachel Karchin, Giovanni Parmigiani
Journal: Genome biology (2011)

We introduce and evaluate data analysis methods to interpret simultaneous measurement of multiple genomic features made on the same biological samples. Our tools use gene sets to provide an interpretable common scale for diverse genomic information. We show we can detect genetic effects, although they may act through different mechanisms in different samples, and show we can discover and validate important disease-related gene sets that would not be discovered by analyzing each data type individually.
Assessing theory of mind with nonverbal procedures: Problems with training methods and an alternative “key” procedure
Authors: Juan Carlos Gómez
Journal: Behavioral and Brain Sciences (1998)

This commentary criticizes nonverbal methods of assessing theory-of-mind on the basis of prior training of the critical response because they would encourage simple, nonmentalistic, associative solutions even in subjects with mentalistic capacities. I propose instead a new experimental paradigm based upon the use of spontaneous responses in less artificial situations. This method has already provided positive evidence of some level of ToM understanding in nonhuman primates.
Orphan nuclear receptor TR3/Nur77 regulates VEGF-A–induced angiogenesis through its transcriptional activity
Authors: Huiyan Zeng, Liuliang Qin, Dezheng Zhao, Xiaolian Tan, Eleanor J. Manseau, Mien Van Hoang, Donald R. Senger, Lawrence F. Brown, Janice A. Nagy, Harold F. Dvorak
Journal: The Journal of Experimental Medicine (2006)

Vascular endothelial growth factor (VEGF)-A has essential roles in vasculogenesis and angiogenesis, but the downstream steps and mechanisms by which human VEGF-A acts are incompletely understood. We report here that human VEGF-A exerts much of its angiogenic activity by up-regulating the expression of TR3 (mouse homologue Nur77), an immediate-early response gene and orphan nuclear receptor transcription factor previously implicated in tumor cell, lymphocyte, and neuronal growth and apoptosis. Overexpression of TR3 in human umbilical vein endothelial cells (HUVECs) resulted in VEGF-A–independent proliferation, survival, and induction of several cell cycle genes, whereas expression of antisense TR3 abrogated the response to VEGF-A in these assays and also inhibited tube formation. Nur77 was highly expressed in several types of VEGF-A–dependent pathological angiogenesis in vivo. Also, using a novel endothelial cell-selective retroviral targeting system, overexpression of Nur77 DNA potently induced angiogenesis in the absence of exogenous VEGF-A, whereas Nur77 antisense strongly inhibited VEGF-A–induced angiogenesis. B16F1 melanoma growth and angiogenesis were greatly inhibited in Nur77−/− mice. Mechanistic studies with TR3/Nur77 mutants revealed that TR3/Nur77 exerted most of its effects on cultured HUVECs and its pro-angiogenic effects in vivo, through its transactivation and DNA binding domains (i.e., through transcriptional activity).
Predicting Steady State Serum Concentrations of Drugs
Authors: D J Greenblatt
Journal: The Annual Review of Pharmacology and Toxicology (1979)

+6745 Mathematical models of biologic processes can be validated both by their abil ity to provide a framework of understanding for already observed phe­ nomena, as well as by prediction of events that have not yet taken place. Clin ical pharmac okinetics is widely accepted as providing useful models for explain ing the behavior of many drugs in the human organism. The predic­ tive value of pharmacok inetic models, however, has been tested less exten­ sively and with somewhat less' success.