tbuckley/cabot-search huggingface dataset:
Abstract 3835: Identification and characterization of inhibitors of 5′-nucleotidase cN-II issued from virtual screening
Authors: Lars P. Jordheim, Zsuzsanna Marton, Moez Rhimi, Laurent Chaloin, Emeline Cros-Perrial, Corinne Lionne, Suzanne Peyrottes, Nushin Aghajari, Charles Dumontet
Journal: Cancer Research (2012)

Abstract Clinical and preclinical observations have lead to the hypothesis that 5′-nucleotidase cN-II could constitute a therapeutic target in oncology, either per se, either to increase the activity of cytotoxic nucleoside analogues. We performed in silico screening of freely available chemical databases, in vitro enzymatic assays with recombinant full length cN-II, soaking experiments with crystals of truncated cN-II and biological evaluation of inhibitors alone or in combination with cytotoxic nucleoside analogues on cancer cells both in vitro and in vivo. The top ranked compounds from virtual screening contained an anthraquinone-derivative (A) and a trisubstituted triazine (B) that were selected for further studies. In vitro enzymatic assay experiments with recombinant protein showed that compound A is a competitive inhibitor with Ki of approximately 3 mM, whereas derivative B is a non-competitive inhibitor with Ki of 1.1 mM. We also obtained crystallographic data at a resolution of 2.0 Å after soaking experiments with crystals of truncated cN-II. These showed interaction between A and F354/N154 situated in the effector site 1 of cN-II, whereas B was not found in crystallographic data even though crystals were degraded in presence of B over a longer time. Derivative A showed different levels of cytotoxicity in vitro on several cancer cell lines such as Raji (IC50=782 µM), RL (IC50=210 µM), CCRF-CEM (IC50=824 µM), MCF-7 (IC50=654 µM), A549 (IC50=569 µM) and HCT-116 (IC50=793 µM), whereas B was much less cytotoxic. When used at 1 mM, A and B did not modify IC50 of the nucleoside analogues cladribine, clofarabine or fludarabine in CCRF-CEM cells. When used at 100 µM, compound A increased the induction of apoptosis in RL cells incubated with 0.5 or 1.5 µM cladribine, 0.05 µM clofarabine or 30 µM fludarabine. The administration of A (200 mg/kg, 5d/w, 4w) to mice xenografted with RL cells, induced a delay of tumor development that was higher than in mice treated with fludarabine (50 mg/kg, 1d/w, 4w). We showed that virtual screening can be used for the identification of potent cN-II inhibitors, and we produced clear evidences for the interaction of one inhibitor with the enzyme. Our biological evaluation indicated interesting activity for one lead compound that will be developed further in order to identify candidates with higher biological activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3835. doi:1538-7445.AM2012-3835
A SIMPLE, CHEAP, EFFICIENT GLYCERIN CAPSULE FOR POLYGRAPH
Authors: Morris H. Kahn
Journal: JAMA (1925)

To obtain good pulse waves from a polygraphic apparatus, the simplest method thus far devised is to use a glycerin capsule; i. e., the cup that is applied over the radial pulse is covered with two layers of rubber dam, between which is an amount of glycerin sufficient to bulge the membrane. The apparatus can be made very simply at a cost of not more than 50 cents. All that is required is a thistle tube made of thick glass. This can be obtained for 15 cents at any chemical glass house. Over this is stretched one layer of thick rubber dam held in place by a rubber band. Suction is made and glycerin poured into the cup formation. Another piece of rubber dam is carefully put over this and firmly tied by another rubber band. A strap is made of a piece of. elastic tape cut so as to
Nitric Oxide Synthase Gene Therapy Rapidly Reduces Adhesion Molecule Expression and Inflammatory Cell Infiltration in Carotid Arteries of Cholesterol-Fed Rabbits
Authors: HuSheng Qian, Valentina Neplioueva, Geetha A. Shetty, Keith M. Channon, Samuel E. George
Journal: Circulation (1999)

Background —Hypercholesterolemia reduces nitric oxide bioavailability, manifested by reduced endothelium-dependent vascular relaxation, and also induces vascular adhesion molecule expression and inflammatory cell infiltration. We have previously shown that gene therapy with NO synthase in hypercholesterolemic rabbits substantially reverses the deficit in vascular relaxation. In the present study, we show that NO synthase gene therapy rapidly and substantially reduces vascular adhesion molecule expression, lipid deposition, and inflammatory cell infiltration. Methods and Results —Thirty male New Zealand White rabbits were maintained on a 1% cholesterol diet for 11 to 13 weeks, then underwent carotid artery gene transfer with Ad.nNOS or Ad.βGal (recombinant adenoviruses expressing neuronal NO synthase or β-galactosidase, respectively), or received medium alone in a sham procedure. Arteries were harvested at 1 and 3 days after gene transfer, and the following parameters were determined by immunohistochemical and image-analysis techniques: intercellular adhesion molecule-1, vascular cell adhesion molecule-1, lipid deposition by oil red O staining, lymphocyte infiltration (CD43-positive cells), and monocyte infiltration (RAM-11–positive cells). In Ad.nNOS-treated arteries, all markers were significantly decreased relative to Ad.βGal or sham-treated arteries within 3 days after gene transfer. Ad.nNOS had a particularly striking impact on monocyte infiltration; as early as 24 hours after gene transfer, Ad.nNOS-treated arteries had &gt;3-fold fewer monocytes than Ad.βGal- or sham-treated arteries. Conclusions —NO synthase gene therapy rapidly ameliorates several markers of atherosclerosis in the cholesterol-fed rabbit.
Osteoporosis and Multiple Myeloma-Reply
Authors: Claude N. Lambert
Journal: JAMA (1961)

<h3>To the Editor:—</h3> I think the points that Dr. Mathews brought out are good, especially, in a patient such as the one we were discussing, the point that myeloma of the spine does exist as a diffuse osteoporosis. If there is any indication about this, including the total workup, other studies to prove or disprove multiple myeloma should be done. The Bence-Jones protein is not a consistent finding in multiple myeloma. If it is present, all well and good, but many myeloma cases do not show a positive Bence-Jones protein. The best method of diagnosis is not by serum protein electrophoresis, alkaline and acid phosphatase studies, but by actual bone marrow biopsy.
Abnormally High Serum Acid Phosphatase
Authors: Brooks A. Mick
Journal: JAMA (1972)

To the Editor.—  Several causes of elevated serum acid phosphatase are known, including metastatic carcinoma of the prostate, Gaucher's disease, thrombocytosis, multiple myeloma, and others. Helen Woodard has written extensively about the acid phosphatases. I have seen a patient with a markedly elevated acid phosphatase level due to, as far as I know, a previously unreported cause.  A 24-year-old nurse was seen in employees' clinic for headaches of a migraine-like nature, and found to be hypertensive. She had a family history of thyroid disease, stomach tumors, and was found to have several abnormalities in the laboratory findings, including a mild hypercalcemia, mildly elevated alkaline phosphatase level, and an acid phosphatase level, repeated on several occasions, that was ten times greater than normal. She also had a markedly elevated 5-hydroxyindoleacetic acid. The only abnormality on physical examination was a small breast nodule.  Surgery revealed a hibernoma of the breast and a
The ST3Gal-I Sialyltransferase Controls CD8+ T Lymphocyte Homeostasis by Modulating O-Glycan Biosynthesis
Authors: John J Priatel, Daniel Chui, Nobuyoshi Hiraoka, Collan J.T Simmons, Kevin B Richardson, Dawne M Page, Minoru Fukuda, Nissi M Varki, Jamey D Marth
Journal: Immunity (2000)
Similarities in sequences and cellular expression between rat CD2 and CD4 antigens.
Authors: A F Williams, A N Barclay, S J Clark, D J Paterson, A C Willis
Journal: The Journal of Experimental Medicine (1987)

The MRC OX-34 antigen of rat T lymphocytes was purified and peptide sequences were obtained. Oligonucleotide probes were synthesized and cDNA clones coding for the antigen were isolated and sequenced to yield a predicted protein sequence for the molecule that fitted the peptide data. Comparison of this sequence with that for human CD2 determined by Sewell et al. showed that OX-34 is rat CD2. The primary structure of the molecule was notable for a moderately large cytoplasmic domain of unusual sequence and also for its highly significant relationship to CD4 antigen in the membrane proximal extracellular region and the transmembrane sequence. A relationship to the Ig superfamily can be argued for the two extra cellular domains of CD2, even though neither fits the standard pattern for Ig-related domains. Within the T lymphocyte lineage, rat CD2 seemed to be present on all stages with the exception of approximately 50% of the thymic CD4-,CD8- cells. In addition, the antigen was prominent on most macrophages in the spleen but not found on peritoneal or liver macrophages. CD4 antigen is also expressed on T lymphocytes and macrophages, and thus CD2 and CD4 appear similar in their cellular expression as well as structural characteristics.
STIMULATION OF I<scp>G</scp>G ANTIBODY RESPONSE IN VITRO BY T CELL-REPLACING FACTOR
Authors: A. Schimpl, E. Wecker
Journal: The Journal of Experimental Medicine (1973)

A soluble factor (TRF) produced by mixtures of allogeneic mouse spleen, lymph node, and thymus cells functionally replaces T cells in a primary IgM antibody response to sheep blood cells in vitro. It is now shown that TRF can also reconstitute an IgG antibody response in T cell-deprived spleen cultures derived from preimmunized mice. The optimal time of addition and the amount of TRF required differ between primary and secondary in vitro systems.
Foxp3 expression in CD4+ T cells of patients with systemic lupus erythematosus: a comparative phenotypic analysis
Authors: M Bonelli, K von Dalwigk, A Savitskaya, J S Smolen, C Scheinecker
Journal: Annals of the Rheumatic Diseases (2007)

The forkhead family transcription factor Foxp3 currently represents the most specific marker molecule for CD4(+)CD25(+) T cells with suppressive/regulatory capacity (Treg) in the mouse. Recent studies in the human system, however, indicate that the expression of Foxp3 can be T cell activation dependent. This tempted us to evaluate the significance of Foxp3 expression under autoimmune conditions with chronic T cell activation in patients with systemic lupus erythematosus (SLE) as compared with healthy controls (HCs).Proportions of peripheral blood CD4(+)Foxp3(+) T cells and CD4(+)CD25(high) T cells were determined in patients with active and inactive SLE as compared with HC by flow cytometry. Comparative analysis of the percentage of CD4(+)Foxp3(+) T cells and of percentage of CD4(+)CD25(high) T cells with clinical disease activity and T cell activation marker molecule expression were performed. Finally, the induction of Foxp3 expression was analysed upon T cell activation in vitro.Proportions of CD4(+)Foxp3(+) T cells were significantly increased in patients with SLE as compared with HC and a significant correlation was observed between clinical disease activity and proportions of CD4(+)Foxp3(+) T cells. On the other hand, proportions of CD4(+)CD25(high) were decreased in SLE and no correlation with a T cell activation marker expression of was observed. In addition, in vitro activation of T cells induced Foxp3 expression.Our data suggest that the expression of Foxp3 on CD4(+) T cells in patients with SLE, at least to some extent, reflects the activation of CD4(+) T cells due to underlying disease activity and does not necessarily indicate a functional regulatory T cell capacity.
Management Strategies and Determinants of Outcome in Acute Major Pulmonary Embolism: Results of a Multicenter Registry
Authors: Wolfgang Kasper, Stavros Konstantinides, Annette Geibel, Manfred Olschewski, Fritz Heinrich, Klaus D Grosser, Klaus Rauber, Stein Iversen, Matthias Redecker, Joachim Kienast
Journal: Journal of the American College of Cardiology (1997)
United States bans the execution of "mentally retarded" prisoners
Authors: D. Josefson
Journal: BMJ (2002)

In a landmark decision the US Supreme Court ruled that it is unconstitutional to execute what it terms mentally retarded prisoners.

The decision marks a reversal of a 1989 Supreme Court judgment that there was no national consensus against such executions and that they did not entail “cruel and unusual punishment” or violate the Eighth Amendment of the US Constitution. The new ban will apply to prisoners with IQs of 70 and under.

The six to three ruling, made two weeks ago, involved the case of Atkins v Virginia. In …
Corticosteroids and bone mass in asthma.
Authors: G K Crompton
Journal: BMJ (1987)

just as effective as intravenous prostacyclin in removing the reversible component of pulmonary hypertension in our patients, we regard the use of long term intravenous prostacyclin infusion3 as unnecessary, complicated, dangerous, expensive, and certainly of unproved benefit compared with oral vasodilator therapy.
Multiple IgE‐mediated sensitizations to enzymes after occupational exposure: evaluation by skin prick test, RAST, and immunoblot
Authors: A. Zentner, S. Jeep, R. Wahl, G. Kunkel, J. Kleine‐Tebbe
Journal: Allergy (1997)

We investigated 10 sensitized and 10 nonsensitized workers from a pharmaceutic factory who had been exposed to powdered trypsin, chymotrypsin, bromelain, papain, amylase, and lipase. Ten nonallergic subjects served as a control group. Titrated skin prick tests (SPT), RAST, and immunoblot studies were performed with all six enzymes. SPT reactivity revealed multiple sensitizations to proteolytic enzymes, i.e., papain (specifically sensitized/total number of sensitizations: 9/10), trypsin (8/10), chymotrypsin (8/10), and bromelain (7/10) and appeared to be more frequent and more pronounced than sensitizations to amylase (3/10) or lipase (3/10). The low molecular weight of proteolytic enzymes (20-30 kDa) and their biologic activity might facilitate mucosal penetration more easily and thus-compared to amylase and lipase-permit an immune response and induction of allergic hypersensitivity. Immunoblot studies demonstrated IgG-binding bands in both SPT-positive and -negative workers, indicating exposure to the enzymes, but not in 10 unexposed control subjects. IgE-binding bands of the enzymes were detected only in workers with a positive SPT reaction and/or a positive RAST result. IgG bands were more frequent and the IgG/IgE ratio was increased in workers without allergic complaints compared to symptomatic workers. This might indicate that high levels of specific IgG antibodies to enzymes are associated with an immune response lacking allergic manifestations in spite of IgE-mediated sensitizations to the enzymes. Atopic subjects were at greater risk of developing IgE-mediated sensitization (7/10) and allergic symptoms to enzymes (5/7). However, even without risk of atopy, IgE-mediated hypersensitivity occurred in a few subjects (3/13) exposed to enzymes by inhalation for prolonged periods of time.
Sexuality and Medicine
Authors: Domeena C. Renshaw
Journal: JAMA (1987)

A surprising foreword to this volume by Christie Hefner documents Playboy Enterprise's two decades of dedication to funding research in sexuality, including SIECUS, Masters and Johnson, and this volume. It was a fine investment. There is abundant food for serious thought and clinical application in this multiauthor collection of more than a dozen different essays on various aspects of sexuality. Modern technological fertility practice is now able to "disconnect" conception from coitus. This reality is given careful philosophical review. Past religious and current medical emphasis on the procreative purpose of sexuality may neglect the specifically human needs for emotional nurturance, pair bonding, closeness, trust, and intimacy that constitute loving through sexual exchange. One essay traces the changes in US sexual morality over the past 150 years, from the old and enduring attack on normal masturbation to the sexual permissiveness of the 1970s. Another good essay examines the family physician's role
New infectious diseases will continue to emerge
Authors: D. Singh
Journal: BMJ (2004)

Dozens of new infectious diseases are likely to emerge over the next 25 years unless humans acquire an ecological perspective on infectious diseases rather than seeing microbes as simply an invading entity that should be blindly attacked with antibiotics or used as a tool for biological warfare, a conference was told last week.

Professor Tony McMichael, of the Australian National University, Canberra, said that the emergence and spread of 35 new or newly diagnosed infectious diseases in the past 25 years was a product of our modern way of …
Tetrahydrobiopterin alters superoxide and nitric oxide release in prehypertensive rats.
Authors: F Cosentino, S Patton, L V d'Uscio, E R Werner, G Werner-Felmayer, P Moreau, T Malinski, T F Lüscher
Journal: Journal of Clinical Investigation (1998)

Constitutive nitric oxide synthase (cNOS) with insufficient cofactor (6R)-5,6,7,8-tetrahydrobiopterin (H4B) may generate damaging superoxide (O2-). This study was designed to determine whether cNOS-dependent generation of O2- occurs in spontaneously hypertensive rats (SHR) before the onset of hypertension. Aortas from 4-wk-old SHR and Wistar-Kyoto rats were used. cNOS was stimulated by calcium ionophore A23187. In situ measurements of nitric oxide and hydrogen peroxide by electrochemical sensors and O2- production by chemiluminescence method were performed. Isometric tension was continuously recorded. H4B by high performance liquid chromatography and [3H]citrulline assay were determined in homogenized tissue. The A23187-stimulated production of O2- and its superoxide dismutase product hydrogen peroxide were significantly higher, whereas nitric oxide release was reduced in SHR aortas, with opposite results in the presence of exogenous H4B. Furthermore, NG-monomethyl-L-arginine inhibited the generation of cNOS-dependent O2- by approximately 70%. Natural H4B levels were similar in both strains; however, equivalent cNOS activity required additional H4B in SHR. The endothelium-dependent relaxations to A23187 were significantly inhibited by catalase, and enhanced by superoxide dismutase, only in SHR; however, these enzymes had no effect in the presence of H4B. Thus, dysfunctional cNOS may be a source of O2- in prehypertensive SHR and contribute to the development of hypertension and its vascular complications.
Emergency room medicine: 1
Authors: G. Dunea
Journal: BMJ (1995)

Recent studies have shown that for many Americans the emergency room has become the main source of medical care. This issue has received attention largely in the context of care for the indigent, such care being perceived as unduly expensive, impersonal, episodic, and lacking in continuity. Hurried doctors seeing unfamiliar patients under stressed conditions will always order more tests than an unhurried evaluation of a known patient would require. Dissatisfied patients with unrelieved symptoms often wander on to the next emergency room, where the same tests are likely to be repeated.

Not so with middle class people, goes the prevailing wisdom, for they can contact their doctors at any time …
Mechanical interactions between four heart chambers with and without the pericardium in canine hearts.
Authors: Y Maruyama, K Ashikawa, S Isoyama, H Kanatsuka, E Ino-Oka, T Takishima
Journal: Circulation Research (1982)

By using excised postmortem hearts obtained from 15 mongrel dogs with the pericardium intact, we investigated mechanical interactions between the four heart chambers from the standpoint of ventricular pressure-volume relationships. The interactions investigated were those between (1) the atrium and the ventricle, (2) the right ventricle and left ventricles, (3) the atrium and one ventricle vs. the other ventricle, and finally (4) the left and right atrium and the right ventricle vs. the left ventricle. For these purposes, we inserted compliant balloons into the four heart chambers without injuring the pericardium, i.e., we incised the base of the atria which was not covered with the pericardium. We obtained the right and/or left ventricular pressure-volume relationships under a constant pressure in three other heart chambers by changing the height of the reservoir connected to each balloon. As a result, both ventricular pressure-volume relationships were hardly affected by an increase in the atrial pressure ranging from 5 to 30 cm H2O with the pericardium removed, although the ventricle became less compliant due to an increase of the same magnitude of the opposite ventricular pressure. On the other hand, the effect of an increase in atrial pressure was distinct with the pericardium intact. Also, all mechanical interactions were enhanced dramatically with the intact pericardium. Thus, the pericardium plays an important role in these mechanical interactions, especially when the filling pressures of all heart chambers increase simultaneously. Clinically, these findings may be important to understanding ventricular functions as related to various heart disease-especially acute heart failure.
Letter: HI antibodies to influenza A-Finland-1-74.
Authors: R Pyhala, K Cantell
Journal: BMJ (1974)

recent reports.2It is recommended that potentially lethal infection with Str.pneumoniae or H. influenzae be seriously considered in any asplenic patient with pyrexia which is not readily explaned and, if leucocytosis is found, that treatment with ampicillin be commenced inmmediately after obtaining blood for culture.Asplenuic patients presenting with meningitis or Waterhouse- Friderichsen syndromle should be treated with a regimean including an antibiotic effec- tive against boith Str.pneumoniae and H. influenzae-for example, intravenous am- picillin-until the causal organism has been cldarly identified.
New funding system for adult social care is affordable, says Dilnot
Authors: M. Limb
Journal: BMJ (2011)

The UK government can afford to bring in a new funding system for adult social care and current economic woes should not be an excuse for inaction, says a leading economist.

Andrew Dilnot, whose Commission on Funding of Care and Support reported to ministers earlier this year ( BMJ 2011;343:d4261, doi:10.1136/bmj.d4261), said it was “nonsense” to suggest reform was too expensive.

How much the country spends—as individuals or collectively through the state—was a matter of choice, not affordability, he told the King’s Fund annual conference in London on 23 November.

Mr Dilnot said he …
The PPARα-FGF21 Hormone Axis Contributes to Metabolic Regulation by the Hepatic JNK Signaling Pathway
Authors: Santiago Vernia, Julie Cavanagh-Kyros, Luisa Garcia-Haro, Guadalupe Sabio, Tamera Barrett, Dae Young Jung, Jason K. Kim, Jia Xu, Hennady P. Shulha, Manuel Garber, Guangping Gao, Roger J. Davis
Journal: Cell Metabolism (2014)
IgE-binding and histamine-release capabilities of the main carbohydrate component isolated from the major allergen of olive tree pollen, Ole e 1
Authors: Eva Batanero, Jesús F. Crespo, Rafael I. Monsalve, Manuel Martín-Esteban, Mayte Villalba, Rosalía Rodríguez
Journal: Journal of Allergy and Clinical Immunology (1999)
Primary lymphosarcoma of the lung
Authors: R. L. Hurt, W. P. U. Kennedy
Journal: Thorax (1974)

<b>Hurt, R. L. and Kennedy, W. P. U. (1974).</b><i>Thorax</i>, <b>29</b>, 258-261. <b>Primary lymphosarcoma of the lung.</b> A case report of lymphosarcoma of the lung in a woman aged 69 years. Middle lobectomy was carried out and the diagnosis was made only on subsequent histological examination of the resected lobe. Abnormal immunoglobulins were present in the blood both before operation and one-and-a-half years later, at which time there was a local recurrence.