tbuckley/cabot-search huggingface dataset:
Pharmacological Activation of Soluble Guanylate Cyclase Protects the Heart Against Ischemic Injury
Authors: Sevil Korkmaz, Tamás Radovits, Enikő Barnucz, Kristóf Hirschberg, Philipp Neugebauer, Sivakkanan Loganathan, Gábor Veres, Szabolcs Páli, Beatrice Seidel, Stefan Zöllner, Matthias Karck, Gábor Szabó
Journal: Circulation (2009)

Background— The role of the nitric oxide/cGMP/cGMP–dependent protein kinase G pathway in myocardial protection and preconditioning has been the object of intensive investigations. The novel soluble guanylate cyclase activator cinaciguat has been reported to elevate intracellular [cGMP] and activate the nitric oxide/cGMP/cGMP–dependent protein kinase G pathway in vivo. We investigated the effects of cinaciguat on myocardial infarction induced by isoproterenol in rats. Methods and Results— Rats were treated orally twice a day for 4 days with vehicle or cinaciguat (10 mg/kg). Isoproterenol (85 mg/kg) was injected subcutaneously 2 days after the first treatment at an interval of 24 hours for 2 days to produce myocardial infarction. After 17 hours, histopathological observations and left ventricular pressure-volume analysis to assess cardiac function with a Millar microtip pressure-volume conductance catheter were performed, and levels of biochemicals of the heart tissues were measured. Gene expression analysis was performed by quantitative real-time polymerase chain reaction. Isolated canine coronary arterial rings exposed to peroxynitrite were investigated for vasomotor function, and immunohistochemistry was performed for cGMP and nitrotyrosine. The present results show that cinaciguat treatment improves histopathological lesions, improves cardiac performance, improves impaired cardiac relaxation, reduces oxidative stress, ameliorates intracellular enzyme release, and decreases cyclooxygenase 2, transforming growth factor-β, and β-actin mRNA expression in experimentally induced myocardial infarction in rats. In vitro exposure of coronary arteries to peroxynitrite resulted in an impairment of endothelium-dependent vasorelaxation, increased nitro-oxidative stress, and reduced intracellular cGMP levels, which were all improved by cinaciguat. A cardioprotective effect of postischemic cinaciguat treatment was shown in a canine model of global ischemia/reperfusion. Conclusion— Pharmacological soluble guanylate cyclase activation could be a novel approach for the prevention and treatment of ischemic heart disease.
Effect of continuous enhanced vagal tone on atrioventricular nodal and sinoatrial nodal function in humans.
Authors: R L Page, A S Tang, E N Prystowsky
Journal: Circulation Research (1991)

A constant intravenous infusion of phenylephrine (0.74 +/- 0.41 micrograms/kg/min) was given to 10 patients to cause a continuous augmentation in reflex vagal tone. After the infusion, the diastolic blood pressure increased from 76 +/- 7 to 89 +/- 11 mm Hg (p less than 0.01). The sinus cycle length and atrial-His (AH) interval were measured, and incremental atrial pacing was performed before and during phenylephrine infusion until atrioventricular (AV) nodal block was achieved. For each patient, the AV nodal function curve (i.e., the AH interval plotted as a function of the atrial pacing cycle length) was compared during both the control state and phenylephrine infusion; the AH intervals during each condition at chosen short (AHS) and long (AHL) cycle lengths were compared. The sinus cycle length increased during phenylephrine infusion from 941 +/- 294 to 1,115 +/- 347 msec (p = 0.013). The AH interval during sinus rhythm was not significantly prolonged (77 versus 82 msec, p = NS). The shortest atrial pacing cycle length yielding 1:1 AV nodal conduction increased during phenylephrine infusion from 412 +/- 120 to 575 +/- 211 msec (p less than 0.01). Of note, the degree of sinus cycle length prolongation did not correlate with the degree of prolongation in the shortest atrial pacing cycle length yielding 1:1 AV nodal conduction. The AV nodal function curve was shifted markedly to the right and only slightly upward.(ABSTRACT TRUNCATED AT 250 WORDS)
Concurrent engagement of CD40 and the antigen receptor protects naive and memory human B cells from APO-1/Fas-mediated apoptosis.
Authors: C Lagresle, P Mondière, C Bella, P H Krammer, T Defrance
Journal: The Journal of Experimental Medicine (1996)

Naive and memory B cells were isolated from human tonsils and examined for expression of APO-1/Fas and for their sensitivity to the APO-1-dependent apoptosis. APO-1 was found to be constitutively expressed on memory but not on naive B cells. The susceptibility of both cell types to the APO-1 apoptotic pathway was acquired upon CD40 triggering and was correlated with increased expression of the APO-1 receptor. Both naive and memory B cells were protected from the APO-1-mediated death signal after dual ligation of the Ag receptor adn CD40. Our findings suggest that the APO-1 pathway controls the specificity of B cell responses to T-dependent Ags and that occupancy of the Ag receptor dictates the outcome of APO-1-ligation on B cell survival.
Targeted Inhibition of Inducible Nitric Oxide Synthase Inhibits Growth of Human Melanoma <i>In vivo</i> and Synergizes with Chemotherapy
Authors: Andrew G. Sikora, Alexander Gelbard, Michael A. Davies, Daisuke Sano, Suhendan Ekmekcioglu, John Kwon, Yared Hailemichael, Padmini Jayaraman, Jeffrey N. Myers, Elizabeth A. Grimm, Willem W. Overwijk
Journal: Clinical Cancer Research (2010)

Aberrant expression of inflammatory molecules, such as inducible nitric oxide (NO) synthase (iNOS), has been linked to cancer, suggesting that their inhibition is a rational therapeutic approach. Whereas iNOS expression in melanoma and other cancers is associated with poor clinical prognosis, in vitro and in vivo studies suggest that iNOS and NO can have both protumor and antitumor effects. We tested the hypothesis that targeted iNOS inhibition would interfere with human melanoma growth and survival in vivo in a preclinical model.We used an immunodeficient non-obese diabetic/severe combined immunodeficient xenograft model to test the susceptibility of two different human melanoma lines to the orally-given iNOS-selective small molecule antagonist N(6)-(1-iminoethyl)-l-lysine-dihydrochloride (L-nil) with and without cytotoxic cisplatin chemotherapy.L-nil significantly inhibited melanoma growth and extended the survival of tumor-bearing mice. L-nil treatment decreased the density of CD31+ microvessels and increased the number of apoptotic cells in tumor xenografts. Proteomic analysis of melanoma xenografts with reverse-phase protein array identified alterations in the expression of multiple cell signaling and survival genes after L-nil treatment. The canonical antiapoptotic protein Bcl-2 was downregulated in vivo and in vitro after L-nil treatment, which was associated with increased susceptibility to cisplatin-mediated tumor death. Consistent with this observation, combination therapy with L-nil plus cisplatin in vivo was more effective than either drug alone, without increased toxicity.These data support the hypothesis that iNOS and iNOS-derived NO support tumor growth in vivo and provide convincing preclinical validation of targeted iNOS inhibition as therapy for solid tumors.
Screening for Early Pancreatic Neoplasia in High-Risk Individuals: A Prospective Controlled Study
Authors: Marcia Irene Canto, Michael Goggins, Ralph H. Hruban, Gloria M. Petersen, Francis M. Giardiello, Charles Yeo, Elliott K. Fishman, Kieran Brune, Jennifer Axilbund, Constance Griffin, Syed Ali, Jeffrey Richman, Sanjay Jagannath, Sergey V. Kantsevoy, Anthony N. Kalloo
Journal: Clinical Gastroenterology and Hepatology (2006)
Antitumor Effects of Clinical Dosing Regimens of Bisphosphonates in Experimental Breast Cancer Bone Metastasis
Authors: F. Daubine, C. Le Gall, J. Gasser, J. Green, P. Clezardin
Journal: JNCI Journal of the National Cancer Institute (2007)

Bisphosphonates exhibit direct antitumor activity in animal models, but only at high doses that are incompatible with the clinical dosing regimens approved for the treatment of cancer patients with skeletal metastases. We compared the antitumor effects of clinical dosing regimens of the bisphosphonates zoledronic acid and clodronate in a mouse model of bone metastasis. Mice (n = 6–10 per group) were treated with zoledronic acid, clodronate, or vehicle starting before (preventive protocols) or after (treatment protocols) intravenous injection with human B02/GFP.2 breast cancer cells, which express green fluorescent protein (GFP) and luciferase and metastasize to bone. Zoledronic acid was given as daily, weekly, or single doses at a cumulative dose of 98–100 μg/kg body weight, equivalent to the 4-mg intravenous dose given to patients. Clodronate was given as a daily dose (530 μg/kg/day), equivalent to the daily 1600-mg oral clinical dose given to patients. Bone destruction was measured by radiography, x-ray absorptiometry or tomography, and histomorphometry (as the ratio of bone volume to tissue volume). Skeletal tumor burden was measured by histomorphometry (as the ratio of tumor burden to soft tissue volume [TB/STV]) and luciferase activity. All statistical tests were two-sided. In treatment protocols, daily clodronate was less effective at decreasing the TB/STV ratio than daily (53% versus 87%, difference = 34%, 95% confidence interval [CI] = 16% to 44%, P <.001) or weekly (53% versus 90%, difference = 37%, 95% CI = 19% to 46%, P <.001) zoledronic acid–dosing regimens. Compared with vehicle, a single dose of zoledronic acid decreased tumor burden by only 16% (95% CI = 9% to 22%, P <.001). In preventive protocols, daily clodronate and daily or weekly zoledronic acid decreased the TB/STV ratio by 49% (95% CI = 40% to 57%, P = .006), 83% (95% CI = 68% to 98%, P <.001), and 66% (95% CI = 47% to 84%, P <.001), respectively, compared with vehicle, whereas a single dose of zoledronic acid decreased tumor burden by only 13% (95% CI = −2% to 28%, P = .84). Mice treated with a daily preventive regimen of clodronate or with a daily or weekly preventive regimen of zoledronic acid showed a decreased B02/GFP.2 cell tumor burden compared with vehicle, whereas a single preventive dose of zoledronic acid had no effect. Daily or repeated intermittent therapy with clinical doses of bisphosphonates inhibits skeletal tumor growth in a mouse model.
Stress-Induced and Fear Circuitry Disorders: Advancing the Research Agenda for DSM-Vedited by AndrewsGavin , CharneyDennis S. , SirovatkaPaul J. , RegierDarrel A. . Washington, D.C. American Psychiatric Publishing, Inc., 2009, 330pp., $60.00
Authors: Dewleen Baker
Journal: American Journal of Psychiatry (2010)
Human Kidney Injury Molecule-1 Is a Tissue and Urinary Tumor Marker of Renal Cell Carcinoma
Authors: Won K. Han, Anwar Alinani, Chin-Lee Wu, Dror Michaelson, Massimo Loda, Francis J. McGovern, Ravi Thadhani, Joseph V. Bonventre
Journal: Journal of the American Society of Nephrology (2005)

Human kidney injury molecule-1 (hKIM-1) is a type 1 transmembrane protein that is not detectable in normal kidney tissue but is expressed at high levels in human and rodent kidneys with dedifferentiated proximal tubule epithelial cells after ischemic or toxic injury. Therefore, it was hypothesized that renal tumors express hKIM-1 and release this protein into the urine. Forty renal cell carcinoma (RCC) and 484 nonrenal tumors were analyzed by immunohistochemistry for expression of hKIM-1 (group 1). Urine samples before nephrectomy and nephrectomy tissue samples were collected from an additional 42 patients with renal tumors, from 30 normal control subjects, and also from 10 patients with prostate carcinoma (group 2). In five additional patients with RCC, urine was collected before and after nephrectomy (group 3). Tissue was examined for expression of hKIM-1, and cell-free urine supernatants were analyzed for hKIM-1 by ELISA. Urinary hKIM-1 was normalized to the urinary creatinine concentration (UCr). Expression of hKIM-1 was present in 32 tissue sections (91%) of 35 clear cell RCC (group 1). In group 2, the normalized urinary hKIM-1 levels were significantly higher in patients with clear cell RCC (0.39 ± 0.08 ng/mg UCr; n = 21), compared with levels in patients with prostate carcinoma (0.12 ± 0.03 ng/mg UCr; P < 0.02; n = 10), or normal control subjects (0.05 ± 0.01 ng/mg UCr; P < 0.005; n = 30). Tissue sections from 28 (82%) of 34 primary RCC stained positively for the expression of hKIM-1. In all patients with a detectable prenephrectomy urinary hKIM-1 level, there was either complete disappearance or marked reduction after nephrectomy (group 3). In conclusion, the cleaved ectodomain of hKIM-1 can be detected in the urine of patients with RCC and may serve as a new biomarker for early detection of RCC.
Hypersensitivity reactions in small intestine. I Thymus dependence of experimental 'partial villous atrophy'.
Authors: A Ferguson, E E Jarrett
Journal: Gut (1975)

Rats infected with the intestinal nematode Nippostrongylus brasiliensis have crypt hyperplasia with villous atrophy in affected areas of the small intestine. In thymus-deprived (B) rats the course of infection is prolonged but, despite the presence of many worms in the intestinal lumen, villi and crypts appear largely normal. This suggests that the tissue damaged associated with N. brasilliensis infection is caused, not by the worms, but by a local thymus-dependent immune reaction. There is some evidence to implicate lymphocytes rather than antibodies in this reaction. It is already know that T-cell-associated damage to the small intestine, such as occurs in allograft rejection, produces subtotal villous atrophy. The present findings suggest that when T cell react locally with helminth antigens a similar type of damage occurs. The presence of a local cell-mediated immune reaction may be the common factor which causes villous atrophy and crypt hyperplasia in many small intestinal diseases, eg, viral enteritis, giardiasis, cow's milk allergy, and coeliac disease.
Doping in sport. Global ethical issues
Authors: G Bryant
Journal: British Journal of Sports Medicine (2008)

Edited by Angela Schneider, Fan Hong. . Published by Taylor & Francis (Routledge) Colchester, 2007, pp 199, £21.99 (softcover). ISBN 9780415352239

This text is part of a series called “Sport in the Global Society”. It contains 10 essays from different contributors that discuss and debate ethical issues and arguments about performance enhancing drugs in sport in a global context. As the introduction says, “the perspectives covered range from athletes to administrators, from specific countries to the international community and from scepticism to optimism.”

The fairness, values and ethics of anti-doping policies and application in different countries and internationally are discussed. The specific countries are: USA, Argentina, UK, France (Tour de France), Bulgaria (Bulgarian Weightlifting Association), Japan, China, Norway …
Impaired regulation of NF-κB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice
Authors: Jun Zhang, Brigid Stirling, Stephane T. Temmerman, Chi A. Ma, Ivan J. Fuss, Jonathan M.J. Derry, Ashish Jain
Journal: Journal of Clinical Investigation (2006)

Cylindromatosis (CYLD) is a deubiquitinating enzyme that is altered in patients with familial cylindromatosis, a condition characterized by numerous benign adnexal tumors. However, the regulatory function of CYLD remains unsettled. Here we show that the development of B cells, T cells, and myeloid cells was unaffected in CYLD-deficient mice, but that the activation of these cells with mediators of innate and adaptive immunity resulted in enhanced NF-κB and JNK activity associated with increased TNF receptor–associated factor 2 (TRAF2) and NF-κB essential modulator (NEMO) ubiquitination. CYLD-deficient mice were more susceptible to induced colonic inflammation and showed a dramatic increase in the incidence of tumors compared with controls in a colitis-associated cancer model. These results suggest that CYLD limits inflammation and tumorigenesis by regulating ubiquitination in vivo.
Neoadjuvant phase II multicentre study of new agents in patients with malignant glioma after minimal surgery. Report of a cohort of 187 patients treated with temozolomide
Authors: M. Brada, S. Ashley, A. Dowe, A. Gonsalves, A. Huchet, G. Pesce, M. Reni, F. Saran, B. Wharram, M. Wilkins, P. Wilkins
Journal: Annals of Oncology (2005)
Alpha 1-adrenoceptor-mediated phosphoinositide breakdown and inotropic response in rat left ventricular papillary muscles.
Authors: H Otani, H Otani, D K Das
Journal: Circulation Research (1988)

alpha 1-Adrenoceptor stimulation of rat left ventricular papillary muscles by phenylephrine in the presence of propranolol resulted in rapid breakdown of phosphatidylinositol 4,5-bisphosphate (PI-4,5-P2) and a triphasic inotropic response in a concentration-dependent manner. The release of inositol trisphosphate (IP3) was maximum within 30 seconds and remained high for at least 30 minutes. The IP3 formation was associated with a rapid, but small, increase in contractile force followed by a transient decline in the contractility prior to the development of a sustained and more pronounced positive inotropic response. Inhibition of PI-4,5-P2 hydrolysis by the alpha 1-adrenergic antagonist prazosin or the PI-4,5-P2 phosphodiesterase inhibitor neomycin blocked all components of the inotropic responses. Combined addition of 2,3-diphosphoglyceric acid, a competitive inhibitor of IP3 phosphatase, with phenylephrine doubled the IP3 formation and potentiated the initial phases of inotropic responses but had no effect on the sustained positive inotropic response. Nifedipine and Mn2+ did not block the transient inotropic responses but inhibited the sustained positive inotropic response. alpha 1-Adrenoceptor stimulation resulted in restoration of slow responses in the high K+-depolarized muscles in the time course similar to that of the development in the sustained positive inotropic response. Addition of phorbol-12,13-dibutyrate alone or in combination with caffeine or A23187 failed to produce a sustained positive inotropic effect, but pretreatment with this phorbol ester (1-100 nM) for 30 minutes resulted in dose-dependent potentiation of alpha 1-adrenoceptor-mediated sustained positive inotropic effect associated with enhanced slow responses. These results suggest that the inotropic effects mediated by cardiac alpha 1-adrenoceptor stimulation occur through the phosphodiesteratic cleavage of PI-4,5-P2, such that IP3 may produce transient inotropic effects by mobilizing intracellular Ca2+, while diacylglycerol, along with cofactors that are also generated on alpha 1-adrenoceptor stimulation, may provoke a sustained positive inotropic effect by potentiating slow Ca2+ channels through activation of protein kinase C.
Lectin receptors as markers for Trypanosoma cruzi. Developmental stages and a study of the interaction of wheat germ agglutinin with sialic acid residues on epimastigote cells.
Authors: M E Pereira, M A Loures, F Villalta, A F Andrade
Journal: The Journal of Experimental Medicine (1980)

Trypanosoma cruzi at various stages of maturation and differentiation have been isolated by conventional cellular fractionation procedures and characterized by cell surface markers using 30 highly purified lectins encompassing all known sugar specificities. Cell surface carbohydrates of the various T. cruzi stages were analyzed by agglutination and lectin-binding assays. Specific receptors for wheat germ agglutinin (WGA), Helix pomatia, Sophora japonica, and Bandeiraea simplicifolia lectin II were found only in culture epimastigotes, whereas peanut agglutinin (PNA) sites were present exclusively in amastigotes, those for Phaseolus vulgaris in bloodstream trypomastigotes and amastigotes, and for Wistaria floribunda hemagglutinin predominantly in culture forms of T. cruzi. The N-acetylgalactosamine (DGalNAc)-binding lectin from Bauhinia purpurea agglutinated and inhibited the movement of epimastigotes and bloodstream trypomastigotes, but it only inhibited--without agglutinating--culture trypomastigotes. Because both the agglutination and inhibition of movement were reversed by specific sugar haptens, Bauhinia purpurea sites were present in all the flagellated parasites. On the other hand, PNA sites were detectable on epimastigotes after the cells were treated with sialidase, whereas, at the same time, WGA receptors were completely removed and those for the other sialic acid-binding proteins, Aaptos papillata lectin II and Limulus polyphemus, were partially eliminated; moreover, the activity of Wistaria floribunda hemagglutinin, a DGalNAc-binding lectin, increased 4,000 times. Trypsinization and lyzozyme treatment of epimastigote cells did not significantly affect lectin agglutination or lectin binding. WGA reacted solely with sialic acid residues on epimastigote cell surface with an apparent association constant of 2 x 10(6) M-1, each epimastigote having an estimated average of 3 x 10(6) WGA sites, as determined by binding experiments and a minimum of 7.7 x 10(6) sialic acid residues, as calculated by colorimetric method after sialidase digestion. Evidences are presented that the sialyl residues are rapidly regenerated (in approximately 4 h) and that they, at least for the most part, are not adsorbed from the culture medium. The receptor for the D-mannose-binding lectins (concanavalin A [Con A] and Lens culinaris) must either be on the same carbohydrate moiety having the WGA site, or, if in a distinct molecule, both carrier molecules of Con A and WGA sites must be located close to each other in the plasma membrane of the parasite.
Effects of a Digitalis Glycoside on Coronary and Systemic Dynamics in Conscious Dogs
Authors: STEPHEN F. VATNER, CHARLES B. HIGGINS, DEAN FRANKLIN, EUGENE BRAUNWALD
Journal: Circulation Research (1971)

The effects of ouabain (G-strophanthin), 20 µg/kg were compared in 12 conscious dogs with Doppler flow transducers on the ascending aorta and left circumflex coronary artery and pressure gauges in the aorta, and in 9 of these dogs after general anesthesia with Na pentobarbital. In conscious dogs ouabain caused an initial bradycardia, but heart rate returned almost to control at 15 to 30 minutes, while arterial pressure rose and remained elevated. Cardiac output and coronary blood flow decreased initially, returned to control by 5 minutes and then remained constant. Systemic, mean, and late diastolic coronary resistances were elevated within 1 minute and remained elevated for 30 minutes. After anesthesia, ouabain caused similar increases in arterial pressure and slightly greater increases in systemic resistance, but the bradycardia and reduction of cardiac output were more profound and sustained. In the anesthetized state, coronary resistance rose when heart rate was allowed to slow after ouabain but was not elevated when heart rate was returned to control. Thus, in the conscious state, ouabain caused a distinct elevation in coronary and systemic resistances with no change in cardiac output, while in the anesthetized state ouabain reduced cardiac output and when heart rate was controlled, did not alter coronary resistance.