tbuckley/cabot-search huggingface dataset:
The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial
Authors: Joseph Eron, Patrick Yeni, Joseph Gathe, Vicente Estrada, Edwin DeJesus, Schlomo Staszewski, Philip Lackey, Christine Katlama, Benjamin Young, Linda Yau, Denise Sutherland-Phillips, Paul Wannamaker, Cindy Vavro, Lisa Patel, Jane Yeo, Mark Shaefer
Journal: The Lancet (2006)
Spleen cells from animals tolerant to a thymus-dependent antigen can be activated by lipopolysaccharide to synthesize antibodies against the tolerogen.
Authors: G Möller, E Gronowicz, U Persson, A Coutinho, E Möller, L Hammarström, E Smith
Journal: The Journal of Experimental Medicine (1976)

Immunological tolerance was induced in adult mice by the injection of 5 mg of deaggregated hapten-protein conjugate. The tolerant state was confirmed 4-19 days later by the failure of such animals to mount an immune response against an aggregated form of the same thymus-dependent hapten-protein conjugate as well as by the inability of spleen cells from tolerant animals to respond to a thymus-independent hapten-carrier conjugate. Even though the animals were fully tolerant, their spleen cells were activated by lipopolysaccharide (LPS) in vitro to produce normal numbers of plaque-forming cells against the hapten. The finding that spleen cells from tolerant animals could be activated by LPS into synthesis of antibodies against the tolerogen indicates that tolerance to thymus-dependent antigens does not affect B cells, but presumably only T cells. It is suggested that the only stringent test for the existence of B-cell tolerance is the inability of polyclonal B-cell activators to activate antibody synthesis against the tolerogen. The findings make it unlikely that B-cell tolerance to autologous thymus-dependent antigens exists and further indicate that such antigens cannot deliver activating or tolerogenic signals to B cells, although they are competent to combine with and block the Ig receptors.
Molecular Evolution of the Wound-Induced Serine Protease Inhibitor wip1 in Zea and Related Genera
Authors: Peter Tiffin, Brandon S. Gaut
Journal: Molecular Biology and Evolution (2001)

Plant defense mechanisms have been the subject of intensive investigation. However, little is known about their long-term evolutionary dynamics. We investigated the molecular diversity of a wound-induced serine protease inhibitor, wip1, in the genus Zea, as well as the divergence of wip1 among four genera, Zea, Tripsacum, Sorghum, and Oryza, in order to gain insight into the long-term evolution of plant defense. The specific objectives of this study were to determine (1) whether wip1 has a history of positive or balancing selection, as has been shown for genes involved in plant defense against pathogens, and (2) if the evolutionary histories of wip1 inhibitory loops, which come into closest contact with proteases, differ from the evolutionary history of other parts of this gene. The Zea polymorphism data are consistent with a neutral evolutionary history. In contrast, relative-rate tests suggest a nonneutral evolutionary history. This inconsistency may indicate that selection acting on wip1 is episodic or that wip1 evolves in response to selection favoring novel alleles. We also detected significant heterogeneity in the evolutionary rates of the two inhibitory loops of wip1-one inhibitory loop is highly conserved, whereas the second has diverged rapidly. Because these two inhibitory loops are predicted to have very similar biochemical functions, the significantly different evolutionary histories suggest that these loops have different ecological functions.
Foxp3 Expression in Pancreatic Carcinoma Cells as a Novel Mechanism of Immune Evasion in Cancer
Authors: Sebastian Hinz, Laia Pagerols-Raluy, Hans-Heinrich Oberg, Ole Ammerpohl, Sandra Grüssel, Bence Sipos, Robert Grützmann, Christian Pilarsky, Hendrik Ungefroren, Hans-Detlev Saeger, Günter Klöppel, Dieter Kabelitz, Holger Kalthoff
Journal: Cancer Research (2007)

Abstract The forkhead transcription factor Foxp3 is highly expressed in CD4+CD25+ regulatory T cells (Treg) and was recently identified as a key player in mediating their inhibitory functions. Here, we describe for the first time the expression and function of Foxp3 in pancreatic ductal adenocarcinoma cells and tumors. Foxp3 expression was induced by transforming growth factor-β2 (TGF-β2), but not TGF-β1 stimulation in these cells, and was partially suppressed following antibody-mediated neutralization of TGF-β2. The TGF-β2 effect could be mimicked by ectopic expression of a constitutively active TGF-β type I receptor/ALK5 mutant. Down-regulation of Foxp3 with small interfering RNA (siRNA) in pancreatic carcinoma cells resulted in the up-regulation of interleukin 6 (IL-6) and IL-8 expression, providing evidence for a negative transcriptional activity of Foxp3 also in these epithelial cells. Coculture of Foxp3-expressing tumor cells with naive T cells completely inhibited T-cell proliferation, but not activation, and this antiproliferative effect was partially abrogated following specific inhibition of Foxp3 expression. These findings indicate that pancreatic carcinoma cells share growth-suppressive effects with Treg and suggest that mimicking Treg function may represent a new mechanism of immune evasion in pancreatic cancer. [Cancer Res 2007;67(17):8344–50]
PSYCHIATRY IN THE CANADIAN ARMY
Authors: J. D. M. GRIFFIN, D. G. McKERRACHER, F. S. LAWSON
Journal: American Journal of Psychiatry (1943)

An attempt has been made in this paper to outline the development of the psychiatric service in the Canadian Army. Its organization has been described with particular emphasis on the procedures adopted to meet existing and in some cases unique problems of geography and personnel. It is to be pointed out that this organization is still in the developmental stage. It has been beset with many difficulties and not infrequent criticisms. However, evidences are appearing that some progress is being made and that the way to future progress is clearly marked.
The FIFA medical emergency bag and FIFA 11 steps to prevent sudden cardiac death: setting a global standard and promoting consistent football field emergency care
Authors: Jiri Dvorak, Efraim B Kramer, Christian M Schmied, Jonathan A Drezner, David Zideman, Jon Patricios, Luis Correia, André Pedrinelli, Bert Mandelbaum
Journal: British Journal of Sports Medicine (2013)

Life-threatening medical emergencies are an infrequent but regular occurrence on the football field. Proper prevention strategies, emergency medical planning and timely access to emergency equipment are required to prevent catastrophic outcomes. In a continuing commitment to player safety during football, this paper presents the FIFA Medical Emergency Bag and FIFA 11 Steps to prevent sudden cardiac death. These recommendations are intended to create a global standard for emergency preparedness and the medical response to serious or catastrophic on-field injuries in football.
Role of Cytokine-induced Neutrophil Chemoattractant (CINC) in Ozone-induced Airway Inflammation and Hyperresponsiveness
Authors: HIROSHI KOTO, MICHAEL SALMON, EL-BADOUI HADDAD, TUNG-JUNG HUANG, JOHN ZAGORSKI, K. FAN  CHUNG
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Cytokine-induced neutrophil chemoattractant (CINC) is a rat chemokine with potent chemoattractant effects on neutrophils. We determined the involvement of CINC in ozone-induced airway neutrophilia and bronchial hyperresponsiveness (BHR) in the rat. We found a marked increase in lung CINC messenger RNA (mRNA) within 2 h after cessation of ozone exposure (1 ppm for 3 h), as measured by Northern blot analysis, whereas rats exposed to room air had no detectable CINC mRNA. Ozone exposure induced a significant neutrophilia in bronchoalveolar lavage fluid (BALF) at 24 h after exposure (air-exposed rats: 4.2 ± 2.0 × 104, versus ozone-exposed rats: 16.1 ± 3.7 × 104); prior treatment with a goat anti-CINC antibody (1 mg, intravenously) suppressed the neutrophilia (3.1 ± 0.9 × 104). When administered intratracheally, the antibody (230 μ g) partially inhibited the influx of neutrophils. The increase in bronchial responsiveness to acetylcholine observed after ozone exposure was not inhibited by the anti-CINC antibody. The anti-CINC antibody (1 mg, intravenously) also inhibited BALF neutrophilia induced by exposure to a higher concentration of ozone (3 ppm, 3 h), without an effect on BHR. CINC is an important chemokine causing ozone-induced neutrophil chemoattraction, but is not involved in the induction of ozone-induced BHR. The neutrophil is unlikely to contribute to BHR in this model.
A Novel BH3 Mimetic Reveals a Mitogen-Activated Protein Kinase–Dependent Mechanism of Melanoma Cell Death Controlled by p53 and Reactive Oxygen Species
Authors: Monique Verhaegen, Joshua A. Bauer, Cristina Martín de la Vega, Guoping Wang, Keith G. Wolter, J. Chadwick Brenner, Zaneta Nikolovska-Coleska, Audrey Bengtson, Rajan Nair, James T. Elder, Matt Van Brocklin, Thomas E. Carey, Carol R. Bradford, Shaomeng Wang, María S. Soengas
Journal: Cancer Research (2006)

Abstract The RAS/BRAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway is emerging as a key modulator of melanoma initiation and progression. However, a variety of clinical studies indicate that inhibiting the MAPK pathway is insufficient per se to effectively kill melanoma cells. Here, we report on a genetic and pharmacologic approach to identify survival factors responsible for the resistance of melanoma cells to MEK/ERK antagonists. In addition, we describe a new tumor cell–selective means to bypass this resistance in vitro and in vivo. By generating a panel of isogenic cell lines with specific defects in the apoptotic machinery, we found that the ability of melanoma cells to survive in the absence of functional MEK relies on an ERK-independent expression of the antiapoptotic factor Mcl-1 (and to a lesser extent, Bcl-xL and Bcl-2). Using computer-based modeling, we developed a novel Bcl-2 homology domain 3 (BH3) mimetic. This compound, named TW-37, is the first rationally designed small molecule with high affinity for Mcl-1, Bcl-xL, and Bcl-2. Mechanistic analyses of the mode of action of TW-37 showed a synergistic tumor cell killing in the presence of MEK inhibitors. Importantly, TW-37 unveiled an unexpected role of the MAPK pathway in the control of reactive oxygen species (ROS). This function was critical to prevent the activation of proapoptotic functions of p53 in melanoma cells, but surprisingly, it was dispensable for normal melanocytes. Our results suggest that this MAPK-dependent ROS/p53 feedback loop is a point of vulnerability of melanoma cells that can be exploited for rational drug design. (Cancer Res 2006; 66(23): 11348-59)
The adhesion receptor CD44 promotes atherosclerosis by mediating inflammatory cell recruitment and vascular cell activation
Authors: Carolyn A. Cuff, Devashish Kothapalli, Ijeoma Azonobi, Sam Chun, Yuanming Zhang, Richard Belkin, Christine Yeh, Anthony Secreto, Richard K. Assoian, Daniel J. Rader, Ellen Puré
Journal: Journal of Clinical Investigation (2001)

Atherosclerosis causes most acute coronary syndromes and strokes. The pathogenesis of atherosclerosis includes recruitment of inflammatory cells to the vessel wall and activation of vascular cells. CD44 is an adhesion protein expressed on inflammatory and vascular cells. CD44 supports the adhesion of activated lymphocytes to endothelium and smooth muscle cells. Furthermore, ligation of CD44 induces activation of both inflammatory and vascular cells. To assess the potential contribution of CD44 to atherosclerosis, we bred CD44-null mice to atherosclerosis-prone apoE-deficient mice. We found a 50–70% reduction in aortic lesions in CD44-null mice compared with CD44 heterozygote and wild-type littermates. We demonstrate that CD44 promotes the recruitment of macrophages to atherosclerotic lesions. Furthermore, we show that CD44 is required for phenotypic dedifferentiation of medial smooth muscle cells to the "synthetic" state as measured by expression of VCAM-1. Finally, we demonstrate that hyaluronan, the principal ligand for CD44, is upregulated in atherosclerotic lesions of apoE-deficient mice and that the low-molecular-weight proinflammatory forms of hyaluronan stimulate VCAM-1 expression and proliferation of cultured primary aortic smooth muscle cells, whereas high-molecular-weight forms of hyaluronan inhibit smooth muscle cell proliferation. We conclude that CD44 plays a critical role in the progression of atherosclerosis through multiple mechanisms.
Activity of inhaled lysine acetylsalicylate (L-ASA) on bradykinin-induced bronchoconstriction in asthmatics: evidence of contribution of prostaglandins
Authors: R Polosa, VL Milazzo, S Magri, C Pagano, G Paolino, G Santonocito, G Prosperini, N Crimi
Journal: European Respiratory Journal (1997)

When administered by inhalation, bradykinin provokes dose-related bronchoconstriction in asthmatic subjects by a mechanism believed to involve activation of sensory nerve endings. However, little is known of the change in airway responsiveness to bradykinin after cyclo-oxygenase blockade. The aim of the present study was to investigate the effect of the potent cyclo-oxygenase inhibitor, lysine acetylsalicylate (L-ASA), administered by inhalation, on bradykinin-induced bronchoconstriction in a group of 12 asthmatic subjects. The subjects attended the laboratory on four separate occasions to receive nebulized L-ASA (solution of 90 mg x mL(-1)) or matched placebo (glycine, solution of 30 mg x mL(-1)) 15 min prior to bronchoprovocation tests with bradykinin and methacholine in a randomized, double-blind order with at least a 5 day interval. Changes in airway calibre were followed as forced expiratory volume in one second (FEV1), and responsiveness to agonists was expressed as the provocative concentration causing a 20% fall in FEV1 from baseline (PC20). Administration both of L-ASA and glycine solution caused a small but significant acute fall in FEV1 from baseline, with gradual recovery within 20 min. When compared to placebo, inhaled L-ASA reduced the airway responsiveness to bradykinin in 11 of the 12 subjects studied, the geometric mean (range) values for PC20 bradykinin increasing significantly (p<0.001) by 1.7 doubling dose from 0.55 (0.11-5.05) to 1.72 (0.26-6.05) mg x mL(-1) after placebo and L-ASA, respectively. No significant change in airway responsiveness to methacholine was recorded after L-ASA. It is concluded that administration of lysine acetylsalicylate by inhalation protects the asthmatic airways against bradykinin-induced bronchoconstriction, thus suggesting that endogenous prostaglandins may play a contributory role in the bronchoconstriction to kinins in human asthma.
Slip-Shod or Safely Shod: The Bighorn Sheep as a Natural Model for Research
Authors: D P Manning, J E Cooper, C Jones, M Bruce
Journal: Journal of the Royal Society of Medicine (1990)

Over a million injuries caused by slipping of footwear are believed to require treatment by doctors every year in the United Kingdom and many domestic animals are injured by slipping. Recent research has revealed that surface roughness of solings and floors is an important determinant of grip on lubricated surfaces and it is also known that soling friction is affected by hardness. The bighorn sheep (Ovis canadensis) an animal species which has adapted to a slippery environment, was studied to elucidate optimum roughness and hardness and other features which influence grip. Four adult ewes were examined in the London Zoo. The cloven hooves of this species are very mobile and the cranial tips of the hooves are the first parts to make contact with the ground. A very small contact area ensures penetration of a film of water. Mean roughness of the contact area was found to be 53 microns Rtm and the mean hardness 63 Shore A. These characteristics appear to facilitate an excellent grip on wet slippery rock but not on smooth ice. Further studies of the feet of wild species could contribute to an understanding of the factors which determine the safety of solings and floors.
DNA Vaccines: Immunology, Application, and Optimization
Authors: Sanjay Gurunathan, Dennis M. Klinman, Robert A. Seder
Journal: Annual Review of Immunology (2000)

The development and widespread use of vaccines against infectious agents have been a great triumph of medical science. One reason for the success of currently available vaccines is that they are capable of inducing long-lived antibody responses, which are the principal agents of immune protection against most viruses and bacteria. Despite these successes, vaccination against intracellular organisms that require cell-mediated immunity, such as the agents of tuberculosis, malaria, leishmaniasis, and human immunodeficiency virus infection, are either not available or not uniformly effective. Owing to the substantial morbidity and mortality associated with these diseases worldwide, an understanding of the mechanisms involved in generating long-lived cellular immune responses has tremendous practical importance. For these reasons, a new form of vaccination, using DNA that contains the gene for the antigen of interest, is under intensive investigation, because it can engender both humoral and cellular immune responses. This review focuses on the mechanisms by which DNA vaccines elicit immune responses. In addition, a list of potential applications in a variety of preclinical models is provided.
Purine Receptors in Mammalian Tissues: Pharmacology and Functional Significance
Authors: M Williams
Journal: The Annual Review of Pharmacology and Toxicology (1987)

Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe2+, carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism ...Read More
Role for G <sub>12</sub> /G <sub>13</sub> in Agonist-Induced Vascular Smooth Muscle Cell Contraction
Authors: Antje Gohla, Günter Schultz, Stefan Offermanns
Journal: Circulation Research (2000)

Abstract —Receptor-induced vascular smooth muscle cell contraction is mediated by dual regulation of myosin light chain (MLC 20 ) phosphorylation through Ca 2+ -dependent stimulation of myosin light chain kinase and Rho/Rho-kinase–mediated inhibition of myosin phosphatase. Although myosin light chain kinase regulation is initiated by the coupling of receptors to G proteins of the G q family, G q and G 11 , it is not known how receptors regulate the Rho/Rho-kinase–mediated pathway. In vascular smooth muscle cells, receptor-mediated MLC 20 phosphorylation and cell contraction was blocked by inhibitors of each of the pathways. Receptors of various vasocontractors were found to couple to G q /G 11 and G 12 /G 13 , and constitutively active forms of Gα 12 and Gα 13 induced a pronounced contraction of vascular smooth muscle cells that could be blocked by C3 exoenzyme, by inhibition of Rho-kinase, and by stable analogues of cGMP and cAMP. Receptor-mediated smooth muscle cell contraction was strongly inhibited by dominant-negative forms of Gα 12 and Gα 13 . These data indicate that a G 12 /G 13 -mediated Rho/Rho-kinase–dependent pathway operates in smooth muscle cells and that dual regulation of MLC 20 phosphorylation by vasocontractors is initiated by the dual coupling of their receptors to G proteins of the G q and G 12 families.
A Missense LAMB2 Mutation Causes Congenital Nephrotic Syndrome by Impairing Laminin Secretion
Authors: Ying Maggie Chen, Yamato Kikkawa, Jeffrey H. Miner
Journal: Journal of the American Society of Nephrology (2011)

Laminin β2 is a component of laminin-521, which is an important constituent of the glomerular basement membrane (GBM). Null mutations in laminin β2 (LAMB2) cause Pierson syndrome, a severe congenital nephrotic syndrome with ocular and neurologic defects. In contrast, patients with LAMB2 missense mutations, such as R246Q, can have less severe extrarenal defects but still exhibit congenital nephrotic syndrome. To investigate how such missense mutations in LAMB2 cause proteinuria, we generated three transgenic lines of mice in which R246Q-mutant rat laminin β2 replaced the wild-type mouse laminin β2 in the GBM. These transgenic mice developed much less severe proteinuria than their nontransgenic Lamb2-deficient littermates; the level of proteinuria correlated inversely with R246Q-LAMB2 expression. At the onset of proteinuria, expression and localization of proteins associated with the slit diaphragm and foot processes were normal, and there were no obvious ultrastructural abnormalities. Low transgene expressors developed heavy proteinuria, foot process effacement, GBM thickening, and renal failure by 3 months, but high expressors developed only mild proteinuria by 9 months. In vitro studies demonstrated that the R246Q mutation results in impaired secretion of laminin. Taken together, these results suggest that the R246Q mutation causes nephrotic syndrome by impairing secretion of laminin-521 from podocytes into the GBM; however, increased expression of the mutant protein is able to overcome this secretion defect and improve glomerular permselectivity.
Effects of basic fibroblast growth factor on bone formation in vitro.
Authors: E Canalis, M Centrella, T McCarthy
Journal: Journal of Clinical Investigation (1988)

Basic fibroblast growth factor (bFGF) was studied for its effects on bone formation in cultured rat calvariae. bFGF at 0.1-100 ng/ml stimulated [3H]thymidine incorporation into DNA by up to 4.4-fold. bFGF also increased the number of colcemid-induced metaphase arrested cells and the DNA content. Transient (24 h) treatment with bFGF enhanced [3H]-proline incorporation into collagen 24-48 h after the factor was removed; this effect was DNA synthesis dependent and blocked by hydroxyurea. The collagen stimulated by bFGF was type I, and this effect was observed primarily in the periosteum-free bone. In contrast, continuous treatment with bFGF for 24-96 h inhibited [3H]proline incorporation into type I collagen. bFGF did not alter collagen degradation. In conclusion, bFGF stimulates calvarial DNA synthesis, which causes an increased number of collagen-synthesizing cells, but bFGF has a direct inhibitory effect on collagen synthesis.