tbuckley/cabot-search huggingface dataset:
Platelet aggregation inhibitory effects of the new positive inotropic agents pimobendan and UD CG 212 in whole blood
Authors: A. R SANIABADI, G. D LOWE, J. J BELCH, C. D FORBES
Journal: Cardiovascular Research (1989)

A method is described for studying platelet function in human whole blood immediately after venepuncture in order to evaluate the antithrombotic potential of new pharmacological agents. In this method, platelet aggregation is quantified by measuring the fall in single platelet count, by using a whole blood platelet counter. We have investigated the platelet aggregation inhibitory effects of the new positive inotropic agents pimobendan and UD CG 212 (reported to be Ca++ sensitisers and phosphodiesterase inhibitors), alone and in combination with dipyridamole. Venous blood was drawn directly into prewarmed (37 degrees C) plastic syringes containing anticoagulants (3.2% trisodium citrate solution) plus a platelet aggregation inhibitor. Spontaneous platelet aggregation (SPA) was studied by roller mixing aliquots of blood in the collecting syringes for 6 min at 37 degrees C. Collagen induced platelet aggregation was studied by incubating aliquots of blood with 1 microgram/ml collagen on a shaking water bath for 3 min. In the absence of an inhibitor, there was a 50% fall in single platelet count due to SPA and a 65% fall was induced by collagen. Both SPA and collagen induced aggregation responses were inhibited by pimobendan (0.5-10 microM) and UD CG 212 (0.5-10 microM), in a dose dependent manner. A combination of 10 microM dipyridamole with 2 microM pimobendan or UD CG 212 was markedly a more effective inhibitor of platelet aggregation than a high dose of either inhibitor alone. It is suggested that the present method is simple and rapid, with minimal sample processing, and therefore the results may be protected from serious artifacts.(ABSTRACT TRUNCATED AT 250 WORDS)
Visual Recovery in Treated Bacterial Keratitis
Authors: Muthiah Srinivasan, Jeena Mascarenhas, Revathi Rajaraman, Meenakshi Ravindran, Prajna Lalitha, Kathryn J. Ray, Michael E. Zegans, Nisha R. Acharya, Thomas M. Lietman, Jeremy D. Keenan
Journal: Ophthalmology (2014)
Bronchodilation test in COPD: effect of inspiratory manoeuvre preceding forced expiration
Authors: P. Santus, M. Pecchiari, P. Carlucci, B. Boveri, F. Di Marco, F. Castagna, S. Centanni
Journal: European Respiratory Journal (2003)

The effects of an inspiratory manoeuvre preceding forced expiration on functional tests performed under routine conditions before and after inhalation of a bronchodilator drug (salbutamol) were assessed on 150 consecutive chronic obstructive pulmonary disease outpatients. The patients performed forced vital capacity manoeuvres either immediately after a rapid inspiration (manoeuvre no. 1) or after a slow inspiration with a 4–6 s pause (manoeuvre no. 2). Under baseline conditions, forced expiratory volume in one second (FEV 1 ) values were 8% (% control) larger with manoeuvre no. 1 than no. 2. FEV 1 values increased with salbutamol administration by ∼8% and were, on average, still 7% larger with manoeuvre no. 1 than no. 2. The incidence of reversibility, assessed according to American Thoracic Society criteria, was 76% when manoeuvre no. 2 was selected to represent baseline conditions and manoeuvre no. 1 was chosen to represent the effects of bronchodilator administration, whereas the lowest incidence (2%) was found when manoeuvre no. 1 was selected to represent baseline conditions and manoeuvre no. 2 was chosen to represent the effects of bronchodilator administration. These results indicate that the time dependence of the forced vital capacity manoeuvre has an important impact on the assessment of routine lung function in a clinical setting and supports the notion that the time course of the inspiration preceding the forced vital capacity manoeuvre should be standardised.
The effect of prelung transplant clinical status on post-transplant survival of children with cystic fibrosis
Authors: P. Aurora, A Gassas, S. Ehtisham, B. Whitehead, P. Whitmore, P.G. Rees, V.T. Tsang, M.J. Elliott, M. de Leval
Journal: European Respiratory Journal (2000)

The aim of this study was to determine whether transplanting paediatric cystic fibrosis (CF) patients later in the course of their disease was detrimental to their post-transplant survival. Data was collected from 51 children with CF undergoing lung or heart-lung transplantation May 1988-March 1999. The following risk factors were tested by Cox proportional hazards modelling: age at transplant; sex; donor/recipient sex mismatch; donor/recipient cytomegalovirus (CMV) mismatch; cold and warm graft ischaemic times; and donor age. Pretransplant forced expiratory volume in one second (FEV1), minimum oxygen saturation obtained during 12 min walk (Sa,O2min), and a survival probability score (SP) calculated from FEV1, age adjusted resting heart rate, age, sex, blood haemoglobin (Hb), and serum albumin were then added to the model. None of the risk factors were significantly correlated with death during the study period. No evidence that clinical status prior to transplant has any effect upon the post-transplant survival of children with cystic fibrosis was found.
Cyclooxygenase as a Target in Lung Cancer
Authors: Joanne R. Brown, Raymond N. DuBois
Journal: Clinical Cancer Research (2004)

Abstract Preclinical studies suggest that cyclooxygenase (COX)-2 may be involved in the molecular pathogenesis of some types of lung cancer. Most of the available studies point to its involvement in non-small cell lung cancer. Survival of patients with non-small cell lung cancer expressing high levels of COX-2 is markedly reduced. Treatment of humans with the selective COX-2 inhibitor celecoxib augments the antitumor effects of chemotherapy in patients with non-small cell lung cancer. COX-2 has been shown to regulate some aspects of tumor-associated angiogenesis. Most of the results we have published point to effects on the regulation of vascular endothelial growth factor. However, prostaglandins derived from COX-2 affect other signaling pathways as well, such as the epidermal growth factor and its receptor. Others have recently shown that non-small cell lung cancer exhibits a COX-2 downstream enzyme expression pattern that is altered in lung tumor cells and tumor-supplying vessels. Therefore, COX-2 and prostaglandins may have a major impact on lung tumor progression and tumor-associated inflammation. Clinical trials currently underway are exploring the potential of targeting COX-2 in lung cancer.
Effect of thyroid-suppressive doses of triiodothyronine on thyroxine turnover and on the free thyroxine fraction
Authors: George C. Schussler, Vernon K. Vance
Journal: Journal of Clinical Investigation (1968)

The relationship between free thyroxine concentration and thyroxine turnover was studied during thyroid suppression with triiodothyronine. Although there was some increase in the proportion of serum thyroxine bound to thyroxine-binding globulin, the ratio of ultrafilterable to protein-bound hormone was not significantly affected. The fractional disappearance rate of thyroxine increased from an average control value of 11.47%/day to 14.72%/day. Because of contraction of the thyroxine distribution space the clearance of thyroxine was less markedly affected, increasing from 1.37 to 1.56 liters/day. Since the ratio of thyroxine turnover to free thyroxine concentration, i.e., the free thyroxine clearance, increased proportionately (4.79-5.55 liters x 10(3)/day) we conclude that triiodothyronine stimulates thyroxine clearance by a mechanism that is independent of effects on free thyroxine concentration.
Therapeutic Potential of<i>α</i>7 Nicotinic Acetylcholine Receptors
Authors: Daniel Bertrand, Chih-Hung L. Lee, Dorothy Flood, Fabrice Marger, Diana Donnelly-Roberts
Journal: Pharmacological Reviews (2015)

Progress in the fields of neuroscience and molecular biology has identified the forebrain cholinergic system as being important in many higher order brain functions. Further analysis of the genes encoding the nicotinic acetylcholine receptors (nAChRs) has highlighted, in particular, the role of <i>α</i>7 nAChRs in these higher order brain functions as evidenced by their peculiar physiologic and pharmacological properties. As this receptor has gained the attention of scientists from academia and industry, our knowledge of its roles in various brain and bodily functions has increased immensely. We have also seen the development of small molecules that have further refined our understanding of the roles of <i>α</i>7 nAChRs, and these molecules have begun to be tested in clinical trials for several indications. Although a large body of data has confirmed a role of <i>α</i>7 nAChRs in cognition, the translation of small molecules affecting <i>α</i>7 nAChRs into therapeutics has to date only progressed to the stage of testing in clinical trials. Notably, however, most recent human genetic and biochemical studies are further underscoring the crucial role of <i>α</i>7 nAChRs and associated genes in multiple organ systems and disease states. The aim of this review is to discuss our current knowledge of <i>α</i>7 nAChRs and their relevance as a target in specific functional systems and disease states.
The Amiens Strategy: Small Phase III Trials for Clinically Relevant Progress in the War Against Cancer
Authors: John J.L. Jacobs, Dainius Characiejus, Rik J. Scheper, Rachel J.E. Stewart, Jurgen F.V. Tan, Radosveta Tomova, Zachary Krastev, Willem Den Otter
Journal: Journal of Clinical Oncology (2009)
Generation of medaka gene knockout models by target-selected mutagenesis.
Authors: Yoshihito Taniguchi, Shunichi Takeda, Makoto Furutani-Seiki, Yasuhiro Kamei, Takeshi Todo, Takao Sasado, Tomonori Deguchi, Hisato Kondoh, Josine Mudde, Mitsuyoshi Yamazoe, Masayuki Hidaka, Hiroshi Mitani, Atsushi Toyoda, Yoshiyuki Sakaki, Ronald HA Plasterk, Edwin Cuppen
Journal: Genome biology (2006)

Abstract We have established a reverse genetics approach for the routine generation of medaka ( Oryzias latipes ) gene knockouts. A cryopreserved library of N -ethyl- N -nitrosourea (ENU) mutagenized fish was screened by high-throughput resequencing for induced point mutations. Nonsense and splice site mutations were retrieved for the Blm , Sirt1 , Parkin and p53 genes and functional characterization of p53 mutants indicated a complete knockout of p53 function. The current cryopreserved resource is expected to contain knockouts for most medaka genes.
Aspirin for the Primary Prevention of Cardiovascular Events
Authors: Andrew D. Calvin, Niti R. Aggarwal, Mohammad Hassan Murad, Qian Shi, Mohamed B. Elamin, Jeffrey B. Geske, M. Merce Fernandez-Balsells, Felipe N. Albuquerque, Julianna F. Lampropulos, Patricia J. Erwin, Steven A. Smith, Victor M. Montori
Journal: Diabetes Care (2009)

OBJECTIVE The negative results of two randomized controlled trials (RCTs) have challenged current guideline recommendations for using aspirin for primary prevention of cardiovascular events among patients with diabetes. We therefore sought to determine if the effect of aspirin for primary prevention of cardiovascular events and mortality differs between patients with and without diabetes. RESEARCH DESIGN AND METHODS We conducted a systematic search of MEDLINE, EMBASE, Cochrane Library, Web of Science, and Scopus since their inceptions until November 2008 for RCTs of aspirin for primary prevention of cardiovascular events. Blinded pairs of reviewers evaluated studies and extracted data. Random-effects meta-analysis and Bayesian logistic regression were used to estimate the ratios of relative risks (RRs) of outcomes of interest among patients with and without diabetes. A 95% CI that crosses 1.00 indicates that the effect of aspirin does not differ between patients with and without diabetes. RESULTS Nine RCTs with moderate to high methodological quality contributed data to the analyses. The ratios of RRs comparing the benefit of aspirin among patients with diabetes compared with patients without diabetes for mortality, myocardial infarction, and ischemic stroke were 1.12 (95% CI 0.92–1.35), 1.19 (0.82–1.17), and 0.70 (0.25–1.97), respectively. CONCLUSIONS Whereas estimates of benefit among patients with diabetes remain imprecise, our analysis suggests that the relative benefit of aspirin is similar in patients with and without diabetes.
Inhibition of Rho-Associated Kinase Signaling Prevents Breast Cancer Metastasis to Human Bone
Authors: Sijin Liu, Robert H. Goldstein, Ellen M. Scepansky, Michael Rosenblatt
Journal: Cancer Research (2009)

Rho-associated kinase (ROCK) signaling plays a fundamental role in regulating cell morphology, adhesion, and motility. Aberrant expression of ROCK is related to tumor metastases and poor clinical outcome. Here, we show that ROCK expression is increased in metastatic human mammary tumors and breast cancer cell lines compared with nonmetastatic tumors and cell lines. Overexpression of ROCK confers a metastatic phenotype on the nonmetastatic MCF-7 cell line. Inhibition of ROCK activity, by either a specific ROCK inhibitor (Y27632) or ROCK-targeted small interfering RNAs, reduces cell migration and proliferation in vitro and metastasis to bone in vivo using a novel "human breast cancer metastasis to human bone" mouse model. Expression of the c-Myc-regulated miR-17-92 cluster is shown to be elevated in metastatic breast cancer cells compared with nonmetastatic cells and diminished by Y27632 treatment. Furthermore, blockade of miR-17 is shown to decrease breast cancer cell invasion/migration in vitro and metastasis in vivo. Together, these findings suggest that augmented ROCK signaling contributes to breast cancer metastasis. The effects of ROCK on tumor cell invasion/motility and growth may derive from regulating cytoskeletal actin-myosin contraction and modulating the c-Myc pathway, including c-Myc-dependent microRNAs. Inhibition of ROCK or the pathway it stimulates, therefore, may represent a novel approach for treatment of breast cancer metastases.
Innate Immune Pattern Recognition: A Cell Biological Perspective
Authors: Sky W. Brubaker, Kevin S. Bonham, Ivan Zanoni, Jonathan C. Kagan
Journal: Annual Review of Immunology (2015)

Receptors of the innate immune system detect conserved determinants of microbial and viral origin. Activation of these receptors initiates signaling events that culminate in an effective immune response. Recently, the view that innate immune signaling events rely on and operate within a complex cellular infrastructure has become an important framework for understanding the regulation of innate immunity. Compartmentalization within this infrastructure provides the cell with the ability to assign spatial information to microbial detection and regulate immune responses. Several cell biological processes play a role in the regulation of innate signaling responses; at the same time, innate signaling can engage cellular processes as a form of defense or to promote immunological memory. In this review, we highlight these aspects of cell biology in pattern-recognition receptor signaling by focusing on signals that originate from the cell surface, from endosomal compartments, and from within the cytosol.
Tackling asthma phenotypes in community studies
Authors: P. G Gibson
Journal: Thorax (2009)

Episodic wheezing with variable airflow obstruction (asthma) defines a syndrome that is well recognised and much studied. It is now clear that this syndrome is heterogeneous in its clinical features, treatment response, prognosis and pathophysiological mechanisms. Causation remains elusive, yet the differences in asthma prevalence across the world,1 the effect of migration on changing asthma prevalence2 and the rise in asthma prevalence in the past decades highlight very potent gene and environmental effects that modify the clinical expression of asthma.3

Studying asthma heterogeneity is a useful way to disentangle these complex issues.4 The intense focus on allergic mechanisms has given us very precise understanding of the Th2–eosinophil mechanistic pathway, effective and specific treatment—for example, anti-immunoglobulin E (IgE) monoclonal antibody treatment—and shown that a primary prevention strategy based on this approach is not likely to be beneficial.

Current attention is focusing on patterns of granulocyte infiltration, specifically the presence or absence of eosinophils and neutrophils.5 There is clear heterogeneity in these responses among adults with asthma, where a non-eosinophilic pattern of response is associated with more severe persistent asthma, non-response to corticosteroid therapy and certain specific trigger factors such as tobacco smoking and occupational exposures. Furthermore, it is also possible to link the granulocyte response patterns to key immunological mechanisms, such as eosinophils with Th2 lymphocyte responses and neutrophils with dysfunctional innate immune responses.6 This approach integrates basic mechanisms with clinical asthma heterogeneity to yield endogenous asthma phenotypes, or “endotypes”.7

While the application of the …
Expression of ten RGS proteins in human myocardium: functional characterization of an upregulation of RGS4 in heart failure
Authors: Clemens Mittmann, Chin Hee Chung, Grit Höppner, Christina Michalek, Monika Nose, Christian Schüler, Antje Schuh, Thomas Eschenhagen, Joachim Weil, Burkert Pieske, Stephan Hirt, Thomas Wieland
Journal: Cardiovascular Research (2002)

Objective: RGS proteins (regulators of G protein signalling) negatively regulate G protein function as GTPase activating proteins. By controlling heterotrimeric G proteins they may regulate myocardial hypertrophy and contractility. We investigated the expression of RGS proteins in the human heart and whether they take part in the pathophysiological changes of heart failure. Methods and results: Using RNase protection assays (RPAs) RGS2, 3L, 3S, 4, 5 and 6 were identified in the myocardium from terminally failing human hearts with dilated (DCM, n = 22) or ischemic (ICM, n = 18) cardiomyopathy and from nonfailing donor hearts (NF, n = 9). With reverse transcriptase polymerase chain reaction in addition mRNA of RGS1, 9, 12, 14 and 16 were detectable. Compared to NF in failing LV myocardium RGS4 mRNA and protein was upregulated 2–3-fold (mRNA, 10−21 mol/μg±S.E.M.: NF: 22±5§, DCM: 51±10*, ICM: 37±8; §P<0.05 vs. DCM+ICM, *P<0.05 vs. NF, §P<0.05 vs. DCM+ICM; protein, % of NF±S.E.M.: NF: 100±35, DCM 266±60*, ICM: 205±64, n = 5, *P<0.05 vs. NF). In contrast, RGS2, 3L, 3S, 5, 6, and 16 protein and mRNA levels did not vary between failing and NF hearts. In order to investigate the impact of RGS4 on Gq/11 mediated signalling, PLC activity was measured in human LV membranes. Recombinant RGS4 blunted the endothelin-1 (ET-1) stimulated PLC activity. When overexpressed by adenoviral mediated gene transfer in rabbit ventricular myocytes RGS4 abolished the inotropic effect of ET-1. Conclusion: The upregulation of RGS4 in failing human myocardium diminishes Gq/11-mediated signalling and can be involved in the desensitization of Gq/11-mediated positive inotropic effects.
Clinical pharmacokinetics of a placenta‐derived factor XIII concentrate in type I and type II factor XIII deficiency
Authors: Francesco Rodeghiero, Alberto Tosetto, Eros Di Bona, Giancarlo Castaman
Journal: American Journal of Hematology (1991)

Abstract Limited data are available about the pharmacokinetics of placenta‐derived factor XIII (FXIII) concentrate in patients with FXIII deficiency. This concentrate contains only the active subunit A but not the carrier subunit B of the factor, and perplexities have been raised about its clinical use. Moreover, no data are available on its use in the rare patients completely lacking both subunit A and subunit B. Therefore, we evaluated the pharmacokinetics of a commercial placenta concentrate in three patients with FXIII deficiency: two lacking subunit A (type II) and one lacking both subunits (type I). The elimination half‐life of the infused placenta subunit A in the three patients was very similar (280, 283, and 272 hr) and was also consistent with the previously reported data for plasma‐derived FXIII. No thrombin‐independent activity was observed in our concentrate batches. The recovery was significantly lower in the type I patient, in whom infusion of subunit A was not able to elicit a monthly increment of subunit B, as usually observed in type II patients. Monthly infusions of placenta concentrate (at higher dosage in type I patient) have been administered to our patients for two to three years and no evidence of inhibitor against factor XIII activity has been observed. We conclude that placenta concentrates may be as effective as plasma derivatives in replacement therapy of factor XIII deficiency, even in patients who lack subunit B.
Vaccination with Dendritic Cell/Tumor Fusions following Autologous Stem Cell Transplant Induces Immunologic and Clinical Responses in Multiple Myeloma Patients
Authors: Jacalyn Rosenblatt, Irit Avivi, Baldev Vasir, Lynne Uhl, Nikhil C. Munshi, Tami Katz, Bimalangshu R. Dey, Poorvi Somaiya, Heidi Mills, Federico Campigotto, Edie Weller, Robin Joyce, James D. Levine, Dimitrios Tzachanis, Paul Richardson, Jacob Laubach, Noopur Raje, Vassiliki Boussiotis, Yan Emily Yuan, Lina Bisharat, Viki Held, Jacob Rowe, Kenneth Anderson, Donald Kufe, David Avigan
Journal: Clinical Cancer Research (2013)

Abstract Purpose: A multiple myeloma vaccine has been developed whereby patient-derived tumor cells are fused with autologous dendritic cells, creating a hybridoma that stimulates a broad antitumor response. We report on the results of a phase II trial in which patients underwent vaccination following autologous stem cell transplantation (ASCT) to target minimal residual disease. Experimental Design: Twenty-four patients received serial vaccinations with dendritic cell/myeloma fusion cells following posttransplant hematopoietic recovery. A second cohort of 12 patients received a pretransplant vaccine followed by posttransplant vaccinations. Dendritic cells generated from adherent mononuclear cells cultured with granulocyte macrophage colony-stimulating factor, interleukin-4, and TNF-α were fused with autologous bone marrow–derived myeloma fusion cells using polyethylene glycol. Fusion cells were quantified by determining the percentage of cells that coexpress dendritic cell and myeloma fusion antigens. Results: The posttransplant period was associated with reduction in general measures of cellular immunity; however, an increase in CD4 and CD8+ myeloma-specific T cells was observed after ASCT that was significantly expanded following posttransplant vaccination. Seventy-eight percent of patients achieved a best response of complete response (CR)+very good partial response (VGPR) and 47% achieved a CR/near CR (nCR). Remarkably, 24% of patients who achieved a partial response following transplant were converted to CR/nCR after vaccination and at more than 3 months posttransplant, consistent with a vaccine-mediated effect on residual disease. Conclusions: The posttransplant period for patients with multiple myeloma provides a unique platform for cellular immunotherapy in which vaccination with dendritic cell/myeloma fusion fusions resulted in the marked expansion of myeloma-specific T cells and cytoreduction of minimal residual disease. Clin Cancer Res; 19(13); 3640–8. ©2013 AACR.