tbuckley/cabot-search huggingface dataset:
Protease and antiprotease levels in blood of arthritic rats.
Authors: D P Parrott, D A Lewis
Journal: Annals of the Rheumatic Diseases (1977)

Protease, antiprotease, and acid phosphatase blood levels of adjuvant arthritic rats were determined. The protease levels appear to vary inversely with the antiprotease levels. Changes in the protease levels correspond closely to changes in the acid phosphatase levels. Thus it is likely that the lysosomes contribute to the proteases present in the blood. Administered cortisol appears to raise blood antiprotease levels in both normal and arthritic rats and this may reflect an anti-inflammatory action by this drug.
Helicobacter urease–induced activation of the TLR2/NLRP3/IL-18 axis protects against asthma
Authors: Katrin N. Koch, Mara L. Hartung, Sabine Urban, Andreas Kyburz, Anna S. Bahlmann, Judith Lind, Steffen Backert, Christian Taube, Anne Müller
Journal: Journal of Clinical Investigation (2015)

Inflammasome activation and caspase-1–dependent (CASP1-dependent) processing and secretion of IL-1β and IL-18 are critical events at the interface of the bacterial pathogen Helicobacter pylori with its host. Whereas IL-1β promotes Th1 and Th17 responses and gastric immunopathology, IL-18 is required for Treg differentiation, H. pylori persistence, and protection against allergic asthma, which is a hallmark of H. pylori–infected mice and humans. Here, we show that inflammasome activation in DCs requires the cytoplasmic sensor NLRP3 as well as induction of TLR2 signaling by H. pylori. Screening of an H. pylori transposon mutant library revealed that pro–IL-1β expression is induced by LPS from H. pylori, while the urease B subunit (UreB) is required for NLRP3 inflammasome licensing. UreB activates the TLR2-dependent expression of NLRP3, which represents a rate-limiting step in NLRP3 inflammasome assembly. ureB-deficient H. pylori mutants were defective for CASP1 activation in murine bone marrow–derived DCs, splenic DCs, and human blood-derived DCs. Despite colonizing the murine stomach, ureB mutants failed to induce IL-1β and IL-18 secretion and to promote Treg responses. Unlike WT H. pylori, ureB mutants were incapable of conferring protection against allergen-induced asthma in murine models. Together, these results indicate that the TLR2/NLRP3/CASP1/IL-18 axis is critical to H. pylori–specific immune regulation.
Phase II Efficacy and Pharmacogenomic Study of Selumetinib (AZD6244; ARRY-142886) in Iodine-131 Refractory Papillary Thyroid Carcinoma with or without Follicular Elements
Authors: D. Neil Hayes, Amy S. Lucas, Tawee Tanvetyanon, Monika K. Krzyzanowska, Christine H. Chung, Barbara A. Murphy, Jill Gilbert, Ranee Mehra, Dominic T. Moore, Arif Sheikh, Janelle Hoskins, Michele C. Hayward, Ni Zhao, Wendi O'Connor, Karen E. Weck, Roger B. Cohen, Ezra E.W. Cohen
Journal: Clinical Cancer Research (2012)

A multicenter, open-label, phase II trial was conducted to evaluate the efficacy, safety, and tolerability of selumetinib in iodine-refractory papillary thyroid cancer (IRPTC).
Use of combinatorial peptide libraries to construct functional mimics of tumor epitopes recognized by MHC class I-restricted cytolytic T lymphocytes.
Authors: J Blake, J V Johnston, K E Hellström, H Marquardt, L Chen
Journal: The Journal of Experimental Medicine (1996)

Identification of cytolytic T lymphocyte (CTL) epitopes presented by major histocompatibility complex (MHC) class I molecules on tumor cells is critical for the design of active immunotherapy. We describe the use of combinatorial peptide libraries with defined amino acids in two MHC anchor positions to search for epitopes that are recognized by H-2Db- and Kb-restricted CTL specific for the mouse lymphoma EL4. An iterative strategy was used for screening libraries in which 16 amino acids were divided into 3 groups and 3 subgroups: alpha (AL, VT, FY); beta (GS, P, DE); gamma (KR, H, NQ). The proportions of each group and subgroup at individual peptide positions were changed in the library synthesis, and the effect of these changes on CTL activity was measured in a sensitive RMA-S cell assay. A single H-2Db epitope mimic was deduced from the original library that contained > 2 x 10(8) potential peptides and was at least 9 logs more potent than the original library. Immunization of syngeneic mice with this peptide elicited CTL that lysed EL4 cells as well as RMA-S cells pulsed with peptides isolated from Db molecules of EL4 cells, indicating functional similarity between the mimicking peptide and the naturally processed CTL epitope. Furthermore, adoptive transfer of such a CTL line had a therapeutic effect in mice with EL4 established as an ascites tumor. Two H-2Kb-restricted epitope mimics of the same tumor were also identified. Our method represents a novel approach for the construction of MHC class I-restricted targets that can serve as immunogens for active immunotherapy of cancer.
Duty-Hour Limits and Patient Care and Resident Outcomes: Can High-Quality Studies Offer Insight into Complex Relationships?
Authors: Ingrid Philibert, Thomas Nasca, Timothy Brigham, Jane Shapiro
Journal: Annual Review of Medicine (2012)

Long hours are an accepted component of resident education, yet data suggest they contribute to fatigue that may compromise patient safety. A systematic review confirms that limiting duty hours increases residents' hours of sleep and improves objective measures of alertness. Most studies of operative experience for surgical residents found no effect, and there is evidence of a limited positive effect on residents' mood. We find a mixed effect on patient safety, although problems with supervision, rather than the limits, may be responsible or contibute; evidence of reduced continuity of care and reduced continuity in residents' clinical education; and evidence that increased workload under the limits has a negative effect on patient and resident outcomes. We highlight specific areas for research and offer recommendations for national policy.
Combined titre and fluorescent pattern of IgG antinuclear antibodies using cultured cell monolayers in evaluating connective tissue diseases.
Authors: M D Parker, G P Kerby
Journal: Annals of the Rheumatic Diseases (1974)

The Health and Social Care Bill came into force in March after much controversy, but how will we know if it’s good for public health? Zosia Kmietowicz asks doctors, health economists, and policy advisers
Upregulation of T-Helper 1 Cytokines and Chemokine Expression in Post-transplant Airway Obliteration
Authors: ANNETTE BOEHLER, XIAO HUI BAI, MINGYAO LIU, STEPHEN CASSIVI, DEAN CHAMBERLAIN, ARTHUR S. SLUTSKY, SHAF KESHAVJEE
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

The major obstacle to long-term survival after lung transplantation is chronic graft dysfunction manifest as bronchiolitis obliterans. Since the early stages are characterized by proliferation of itinerant cells (lymphocytes and macrophages), we hypothesized that cytokines and chemokines may play a role in the development of the fibroproliferative process. In a heterotopic rat tracheal transplant model, we studied isografts and allografts 3, 7, and 21 d after transplantation as representative time points for the triphasic time course in the evolution of allograft airway obliteration. Using a semiquantitative RT–PCR technique, intragraft gene expression of T-helper 1 (Th1)- and Th2-type cytokines and of C-C and C-X-C chemokines was examined. The results of our study show a distinct pattern of cytokine and chemokine gene expression in the development of post-transplant airway obliteration. Allografts, in contrast to isografts, showed a strong and persistent Th1-type response (expression of interleukin-2 and interferon- γ genes), even after fibrous airway obliteration was complete, suggesting an ongoing allo-immune process until late in the fibroproliferative stage. RANTES and MCP-1 were also upregulated late after transplantation, whereas MIP-2 upregulation occurred early post-transplant and was not restricted to allografts alone, which might reflect alloantigen-independent processes after transplantation that are present in both allografts and isografts.
Driver and Passenger Mutations in Cancer
Authors: Julia R. Pon, Marco A. Marra
Journal: Annual Review of Pathology Mechanisms of Disease (2014)

Next-generation sequencing has allowed identification of millions of somatic mutations and epigenetic changes in cancer cells. A key challenge in interpreting cancer genomes and epigenomes is distinguishing which genetic and epigenetic changes are drivers of cancer development. Frequency-based and function-based approaches have been developed to identify candidate drivers; we discuss the advantages and drawbacks of these methods as well as their latest refinements. We focus particularly on identification of the types of drivers most likely to be missed, such as genes affected by copy number alterations, mutations in noncoding regions, dysregulation of microRNA, epigenetic changes, and mutations in chromatin modifiers.
Effect of nontransmural necrosis on epicardial potential fields. Correlation with fiber direction.
Authors: S Watabe, B Taccardi, R L Lux, P R Ershler
Journal: Circulation (1990)

The effect of nontransmural necrosis on epicardial potential distributions was studied in 13 dogs. In previous studies, left ventricular epicardial pacing generated epicardial potential maps at QRS onset with a negative central area and two positive areas that faced the portions of the wavefront propagating along fibers. Subsequently, the positive areas expanded in a counterclockwise direction by 90 degrees to 120 degrees. In those studies, the rotatory expansion of the positive areas was tentatively attributed to the spread of excitation through deep myocardial layers, where fiber direction rotated counterclockwise from epicardium to endocardium. To test this hypothesis, we tried to interrupt the counterclockwise expansion of the positive area by creating localized, nontransmural necrosis at various depths in the left ventricular wall by injection of formalin or application of laser energy. Epicardial potential maps were obtained from a grid of 12 x 15 electrodes on a 44 x 56-mm area. Epicardial pacing from selected sites generated epicardial maps in which some positive areas were missing compared with controls. The direction of the straight line joining the pacing site to the site of missing positivity correlated well with the average fiber direction in the necrotic mass (r = 0.82, p less than 0.01). Angle between epicardial fiber direction and the straight line described above correlated well with the average depth of the necrosis, expressed as percent of the wall thickness (r = 0.95, p less than 0.01). These data support the hypothesis that the counterclockwise expansion of the epicardial positivity occurring after epicardial pacing results from excitation spreading along deep fibers.(ABSTRACT TRUNCATED AT 250 WORDS)
β <sub>2</sub> Integrin-Dependent Neutrophil Adhesion Induced by Minimally Modified Low-Density Lipoproteins Is Mainly Mediated by F <sub>2</sub> -Isoprostanes
Authors: Luigi Fontana, Cinzia Giagulli, Luciano Cominacini, Anna Fratta Pasini, Pietro Minuz, Alessandro Lechi, Angelo Sala, Carlo Laudanna
Journal: Circulation (2002)

Background— Oxidation of LDL produces a series of biologically active, oxidized lipids. Among them, isoprostanes, and in particular iPF 2α -III, seem to be crucial in mediating some of the key cellular events seen in myocardial ischemia-reperfusion injury. Methods and Results— Minimally modified LDL (MM-LDL) triggers a dose-dependent, very rapid neutrophil adhesion to human fibrinogen. Rapid adhesion triggering correlates with degree of LDL oxidation and accumulation of isoprostanes. Isoprostanes accumulated in MM-LDL are major determinants of the proadhesive effect of oxidized LDL, as shown by experiments of receptor functional deletion. Moreover, evidence is provided of expression on human neutrophils of a biological active isoprostane receptor distinct from the classical thromboxane A 2 receptor. Conclusions— These data suggest that isoprostanes are major contributors to the proadhesive effect induced by MM-LDL on neutrophils and provide additional evidence for the involvement of isoprostanes in the pathogenesis of myocardial ischemia/reperfusion injury.
Imposed intelligibility and strong claims concerning cognitive systems
Authors: Roy Lachman
Journal: Behavioral and Brain Sciences (2004)

The computational hypothesis was formulated with due concern for limits and is consistent with imposed intelligibility doctrines. Theories are products of scientific work that impose human classifications and formalisms on nature. The claim that “cognitive agents are dynamical systems” is untenable. Dynamical formalisms imposed on a natural system, given an approximate fit, serve as an explanatory framework and render a represented system predictable and intelligible.
Proapoptotic BH3-Only BCL-2 Family Protein BIM Connects Death Signaling from Epidermal Growth Factor Receptor Inhibition to the Mitochondrion
Authors: Jing Deng, Takeshi Shimamura, Samanthi Perera, Nicole E. Carlson, Dongpo Cai, Geoffrey I. Shapiro, Kwok-Kin Wong, Anthony Letai
Journal: Cancer Research (2007)

Abstract A subset of lung cancers expresses mutant forms of epidermal growth factor receptor (EGFR) that are constitutively activated. Cancers bearing activated EGFR can be effectively targeted with EGFR inhibitors such as erlotinib. However, the death-signaling pathways engaged after EGFR inhibition are poorly understood. Here, we show that death after inhibition of EGFR uses the mitochondrial, or intrinsic, pathway of cell death controlled by the BCL-2 family of proteins. BCL-2 inhibits cell death induced by erlotinib, but BCL-2–protected cells are thus rendered BCL-2–dependent and sensitive to the BCL-2 antagonist ABT-737. BH3 profiling reveals that mitochondrial BCL-2 is primed by death signals after EGFR inhibition in these cells. As this result implies, key death-signaling proteins of the BCL-2 family, including BIM, were found to be up-regulated after erlotinib treatment and intercepted by overexpressed BCL-2. BIM is induced by lung cancer cell lines that are sensitive to erlotinib but not by those resistant. Reduction of BIM by siRNA induces resistance to erlotinib. We show that EGFR activity is inhibited by erlotinib in H1650, a lung cancer cell line that bears a sensitizing EGFR mutation, but that H1650 is not killed. We identify the block in apoptosis in this cell line, and show that a novel form of erlotinib resistance is present, a block in BIM up-regulation downstream of EGFR inhibition. This finding has clear implications for overcoming resistance to erlotinib. Resistance to EGFR inhibition can be modulated by alterations in the intrinsic apoptotic pathway controlled by the BCL-2 family of proteins. [Cancer Res 2007;67(24):11867–75]
Discordance Between Patient-Predicted and Model-Predicted Life Expectancy Among Ambulatory Patients With Heart Failure
Authors: Larry A. Allen, Jonathan E. Yager, Michele Jonsson Funk, Wayne C. Levy, James A. Tulsky, Margaret T. Bowers, Gwen C. Dodson, Christopher M. O’Connor, G. Michael Felker
Journal: JAMA (2008)

<h3>Context</h3>Patients with chronic heart failure have impaired long-term survival, but their own expectations regarding prognosis have not been well studied.<h3>Objectives</h3>To quantify expectations for survival in patients with heart failure, to compare patient expectations to model predictions, and to identify factors associated with discrepancies between patient-predicted and model-predicted prognosis.<h3>Design, Setting, and Participants</h3>Prospective face-to-face survey of patients from the single-center Duke Heart Failure Disease Management Program between July and December 2004, with follow-up through February 2008. Patient-predicted life expectancy was obtained using a visual analog scale. Model-predicted life expectancy was calculated using the Seattle Heart Failure Model. Actuarial-predicted life expectancy, based on age and sex alone, was calculated using life tables. Observed survival was determined from review of medical records and search of the Social Security Death Index.<h3>Main Outcome Measure</h3>Life expectancy ratio (LER), defined as the ratio of patient-predicted to model-predicted life expectancy.<h3>Results</h3>The cohort consisted of 122 patients (mean age, 62 years; 47% African American, 42% New York Heart Association [NYHA] class III or IV). On average, patients overestimated their life expectancy relative to model-predicted life expectancy (median patient-predicted life expectancy, 13.0 years; model-predicted expectancy, 10.0 years). Median LER was 1.4 (interquartile range, 0.8-2.5). Younger age, increased NYHA class, lower ejection fraction, and less depression were the most significant predictors of higher LER. During a median follow-up of 3.1 years, 29% of the original cohort died. There was no association between higher LER and improved survival (adjusted hazard ratio for overestimated compared with concordant LER, 1.05; 95% confidence interval, 0.46-2.42).<h3>Conclusions</h3>Ambulatory patients with heart failure tended to substantially overestimate their life expectancy compared with model-based predictions for survival. Because differences in perceived survival could affect decision making regarding advanced therapies and end-of-life planning, the causes of these discordant predictions warrant further study.
Utility of HLA Antibody Testing in Kidney Transplantation
Authors: Ana Konvalinka, Kathryn Tinckam
Journal: Journal of the American Society of Nephrology (2015)

HLA antigens are polymorphic proteins expressed on donor kidney allograft endothelium and are critical targets for recipient immune recognition. HLA antibodies are risk factors for acute and chronic rejection and allograft loss. Solid-phase immunoassays for HLA antibody detection represent a major advance in sensitivity and specificity over cell-based methods and are widely used in organ allocation and pretransplant risk assessment. Post-transplant, development of de novo donor-specific HLA antibodies and/or increase in donor-specific antibodies from pretransplant levels are associated with adverse outcomes. Although single antigen bead assays have allowed sensitive detection of recipient HLA antibodies and their specificities, a number of interpretive considerations must be appreciated to understand test results in clinical and research contexts. This review, which is especially relevant for clinicians caring for transplant patients, discusses the technical aspects of single antigen bead assays, emphasizes their quantitative limitations, and explores the utility of HLA antibody testing in identifying and managing important pre- and post-transplant clinical outcomes.
Prognostic Relevance of Response Evaluation Using [<sup>18</sup>F]-2-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography in Patients With Locally Advanced Non–Small-Cell Lung Cancer
Authors: Corneline J. Hoekstra, Sigrid G. Stroobants, Egbert F. Smit, Johan Vansteenkiste, Harm van Tinteren, Pieter E. Postmus, Richard P. Golding, Bonne Biesma, Frans J.H.M. Schramel, Nico van Zandwijk, Adriaan A. Lammertsma, Otto S. Hoekstra
Journal: Journal of Clinical Oncology (2005)

The objective of this study was to determine the accuracy of (early) response measurements using [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG PET) with respect to survival of patients with stage IIIA-N2 non-small-cell lung cancer (NSCLC) undergoing induction chemotherapy (IC), with a comparative analysis of PET methods.In a prospective multicenter study, PET was performed in patients before IC and after one and three cycles. Computed tomography (CT) was performed before and after IC. Glucose consumption (metabolic rate of glucose [MRglu]) was measured using Patlak graphical analysis and correlated with simplified methods. Mediastinal lymph node (MLN) status was assessed visually. Cox proportional hazards analysis was used to determine the prognostic relevance of CT and PET measures of response with respect to survival.Complete PET data sets were available in 47 patients. Median survival was 21 months. MLN status after IC by PET predicted survival (hazard ratio [HR], 2.33; 95% CI, 1.04 to 5.22; P = .04) in contrast with CT (HR, 1.87; 95% CI, 0.81 to 4.30; P = .14). Residual MRglu after IC proved to be the best prognostic factor (HR, 1.95; 95% CI, 1.28 to 2.97; P = .002). Multivariate stepwise analysis showed that PET identified prognostically different strata in patients considered responsive according to CT. Residual MRglu after one cycle selected patients with different outcomes (HR, 2.04; 95% CI, 1.18 to 3.52; P = .01). Simplified quantitative 18FDG PET methods were correlated with Patlak graphical analysis during and after therapy (r > or = 0.90).18FDG PET has additional value over CT in monitoring response to IC in patients with stage IIIA-N2 NSCLC, and it seems feasible to predict survival early during IC. Simple semiquantitative and complex PET methods perform equally well.
Diminished tolerance of prehypertrophic, cardiomyopathic Syrian hamster hearts to Ca2+ stresses.
Authors: O Hano, E G Lakatta
Journal: Circulation Research (1991)

Although abnormal myocardial calcium homeostasis in the cardiomyopathic hamster (CMH) has been documented in the hypertrophic stage of the disease, the Ca2+ tolerance before the hypertrophic stage has not been investigated. We studied isovolumic contractile function in response to a variety of Ca2+ stresses including increases in perfusate [Ca2+] (Cao), the Ca2+ channel agonist Bay K 8644, and alpha- or beta-adrenergic agonists of isolated perfused hamster hearts from 24-45-day-old male CMH, BIO 14.6 strain, and age- and sex-matched F1B strain controls. The coronary flow at a constant perfusion pressure did not differ between two groups at baseline or after any Ca2+ stress. At a Cao of 1.0 mM, neither end-diastolic pressure (EDP) nor developed pressure (DP) nor half relaxation time (RT1/2) during stimulation at 1-3 Hz differed between the two groups; as Cao was increased up to 10 mM, CMH hearts showed a lower threshold for the occurrence of a Ca2+ overload profile: EDP and RT1/2 increased to a greater, and DP to a lesser, extent in CMH than in control hearts. To determine whether calcium influx via Ca2+ channels mediates the lower threshold for Ca2+ overload in CMH hearts, we measured resting pressure and scattered laser light intensity fluctuation (SLIF) in unstimulated hearts. Prior studies have shown that SLIF is generated by microscopic tissue motion caused by diastolic spontaneous sarcoplasmic reticulum Ca2+ release and that SLIF amplitude reflects the extent of cell and sarcoplasmic reticulum Ca2+ loading. The Ca(2+)-dependent increase in resting pressure in unstimulated hearts was highly correlated with an increase in SLIF, and this relation was steeper in CMH than in control hearts. CMH hearts also showed a reduced threshold for the occurrence of a Ca2+ overload profile in response to the adrenergic receptor agonists and the Ca2+ channel agonist during electrical stimulation in a Cao of 2.0 mM: maximum DP achieved with each agonist was significantly less and the dose-response curves to each agonist were shifted leftward in CMH versus control hearts. In CMH hearts EDP began to increase at a significantly lower concentration of each agonist, and the maximum extent of increase in EDP in response to all agonists was significantly enhanced compared with control hearts. In response to beta-adrenergic or Ca2+ channel agonists, neither resting pressure nor SLIF in unstimulated hearts increased in control or in CMH hearts. In contrast, in response to alpha-adrenergic stimulation, both SLIF and resting pressure increased to a greater extent in CMH than in control hearts.(ABSTRACT TRUNCATED AT 400 WORDS)