tbuckley/cabot-search huggingface dataset:
Abstract 5158: Generation of a fully human Gas6 neutralizing antibody with anti-tumor activity <i>in vivo</i>.
Authors: Gordon E. Moody, Brian Belmontes, Chadwick King, Shuying Liu, Stephanie Masterman, Chris Murawsky, Trace Tsuruda, Wei Wang, Robert Radinsky, Pedro J. Beltran
Journal: Cancer Research (2013)

Abstract Growth arrest specific 6 (Gas6) is a vitamin-K dependent protein that is involved in the regulation of a wide array of cellular activities, including adhesion, migration, immune evasion, and apoptosis. Gas6 as well as its receptors Axl, Mer, and Tyro3 are highly expressed in multiple malignancies suggesting that signaling through this axis may be tumor promoting in human disease. A strategy was devised to generate fully human neutralizing antibodies against Gas6 using XenoMouse technology. Hybridoma supernatants were first screened for their ability to bind Gas6, then for their ability to inhibit Gas6 binding to the Axl receptor and block Gas6-induced Axl phosphorylation in human cells. Two purified antibodies isolated from the screened hybridomas, 1D9.1 and 1G9.1, maintained potency in all 3 assays and also inhibited Gas6-induced cellular migration and proliferation. In the scratch wound migration assay, the antibodies inhibited both basal and Gas6-induced wound closure to a greater extent than the soluble extracellular domain of the receptor Axl (Axl- Fc). In the proliferation assay, the antibody 1D9.1 completely inhibited Gas6-induced proliferation with a half maximal effective concentration (EC50) of 0.15nM. In vivo characterization of one of the antibodies, 1D9.1, was conducted using a pharmacodynamic (PD) assay that measured the ability of the antibody to inhibit Gas6-induced Akt activation in the mouse spleen. Treatment of mice with a single dose (100-1000 μg) of 1D9.1 led to greater than 90% inhibition of Gas6-induced phosphorylated Akt (pAkt) for up to 72 hours. Based on the target coverage observed in the PD assay, we tested the efficacy of 1D9.1 against Panc-1 human pancreatic adenocarcinoma xenografts implanted in athymic nu/nu female mice. At doses of 50 and 150 μg, twice weekly, the Gas6 neutralizing antibody 1D9.1 was able to inhibit 55% and 76% of tumor growth, respectively. (p&amp;lt;0.001 for both treatments vs. control Ig). When combined with gemcitabine, 1D9.1 was able to inhibit tumor growth to a greater extent than either agent alone (p&amp;lt;0.001 vs. either monotherapy). Together, the data suggest that Gas6 neutralization should be further explored as a potential strategy for the treatment of pancreatic cancer. Citation Format: Gordon E. Moody, Brian Belmontes, Chadwick King, Shuying Liu, Stephanie Masterman, Chris Murawsky, Trace Tsuruda, Wei Wang, Robert Radinsky, Pedro J. Beltran. Generation of a fully human Gas6 neutralizing antibody with anti-tumor activity in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5158. doi:10.1158/1538-7445.AM2013-5158
Tumor Necrosis Factor-α Inhibits Insulin’s Stimulating Effect on Glucose Uptake and Endothelium-Dependent Vasodilation in Humans
Authors: Christian Rask-Madsen, Helena Domínguez, Nikolaj Ihlemann, Thomas Hermann, Lars Køber, Christian Torp-Pedersen
Journal: Circulation (2003)

Background— Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)-α inhibits insulin-stimulated glucose uptake and insulin-stimulated endothelial function in humans. Methods and Results— Healthy, lean male volunteers were studied. On each study day, 3 acetylcholine (ACh) or sodium nitroprusside (SNP) dose-response studies were performed by infusion into the brachial artery. Before and during the last 2 dose-response studies, insulin and/or TNF-α were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220±44%. This increase was completely inhibited during coinfusion of TNF-α (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow. Furthermore, TNF-α inhibited the ACh forearm blood flow response ( P &lt;0.001), and this inhibition was larger during insulin infusion ( P =0.01) but not further increased by N G -monomethyl- l -arginine acetate ( P =0.2). Insulin potentiated the SNP response less than the ACh response and the effect of TNF-α was smaller ( P &lt;0.001); TNF-α had no effect on the SNP response without insulin infusion. Thus, TNF-α inhibition of the combined response to insulin and ACh was likely mediated through inhibition of NO production. Conclusion— These results support the concept that TNF-α could play a role in the development of insulin resistance in humans, both in muscle and in vascular tissue.
The Responsibility of the Physician in the Selection of Patients with Mitral Stenosis for Surgical Treatment
Authors: DWIGHT E. HARKEN, LAURENCE B. ELLIS, LEWIS DEXTER, ROBERT E. FARRAND, JAMES F. DICKSON
Journal: Circulation (1952)

The anatomy of the mitral leaflets, a classification of the variations in pathologic morphology of rheumatic stenosis, and the evolution of a practical technic for relief of that stenosis while restoring valve action are considered. The life cycle of patients suffering from mitral stenosis is reviewed and a clinical classification of these patients is presented. Some indications and contraindications for surgery are discussed in the light of strength and weakness of present surgical methods. Results of surgical treatment are reviewed.
The Carrying Angle in Sex Chromosome Anomalies
Authors: Fred A. Baughman
Journal: JAMA (1974)

The carrying angle is said to be greater in the XO phenotype than in XX and greater in XX than in XY. To determine the effects of the sex chromosomes on the carrying angle, the angles of chromosomally normal and abnormal patients were compared. Among women, only XO phenotypes did not differ substantially from XX. Among men, all comparisons showed a considerable difference, with the difference between XY and XYY phenotypes being highly significant. In sex chromosome aneuploidy, there appears to be a spectrum of elbow abnormalities with maximal cubitus valgus in XO phenotypes at one extreme, decreasing degrees of valgus in XX and XY, and approaching cubitus rectus in cases with one supernumerary X or Y, with cubitus varus and radioulnar synostosis and radial head dislocation where there are multiple supernumerary sex chromosomes. (<i>JAMA</i>230:718-720, 1974)
Reply to Joan Palou, Óscar Rodríguez and Alberto Breda’s Letter to the Editor re: Markus J. Bader, Ronald Sroka, Christian Gratzke, et al. Laser Therapy for Upper Urinary Tract Transitional Cell Carcinoma: Indications and Management. Eur Urol 2009;56:65–71
Authors: Markus J. Bader, Oliver Reich, Christian G. Stief, Christian Gratzke
Journal: European Urology (2009)
Evolution of mammalian X-linked and autosomal Pgk and Pdh E1 alpha subunit genes
Authors: J. Fitzgerald, H. H. Dahl, I. B. Jakobsen, S. Easteal
Journal: Molecular Biology and Evolution (1996)

The phylogeny and substitution rates of the mammalian X chromosome-located and autosomal phosphoglycerate kinase and pyruvate dehydrogenase genes were investigated. Compatibility analysis was used to show reticulate evolution in these genes. Analysis of the marsupial, mouse, and human phosphoglycerate kinase genes suggests that at least two recombination events have taken place, one occurring about the time of the placental-marsupial split involving exons 1-5 and the other before the primate-rodent split involving exons 9-10. Similar analysis of the pyruvate dehydrogenase genes indicates a recombination event involving exons 2-3 at a time before the primate-rodent split and a gene conversion between exons 3-4 in the human somatic and testis-specific pyruvate dehydrogenase genes after the primate-rodent split. This demonstrates that genetic exchange can occur between paralogous genes at widely separated chromosomal locations. Estimation of nucleotide substitution rates in these genes confirmed a higher substitution rate in the pyruvate dehydrogenase genes. In the phosphoglycerate kinase genes, there is no difference between the substitution rates in mice and humans and between the X chromosome- and autosome-located genes. A greater substitution rate was noted in the mouse autosomal pyruvate dehydrogenase gene when compared with the other mouse and human genes. This may be a result of either directional natural selection or a relaxation of functional constraint at this specific gene.
Influence of Socioeconomic and Cultural Factors on Racial Differences in Late-Stage Presentation of Breast Cancer
Authors: Donald R. Lannin
Journal: JAMA (1998)

Context.—Breast cancer mortality is higher among African American women than among white women in the United States, but the reasons for the racial difference are not known.Objective.—To evaluate the influence of socioeconomic and cultural factors on the racial difference in breast cancer stage at diagnosis.Design.—Case-control study of patients diagnosed as having breast cancer at the University Medical Center of Eastern Carolina from 1985 through 1992.Setting.—The major health care facility for 2 rural counties in eastern North Carolina.Subjects.—Five hundred forty of 743 patients with newly diagnosed breast cancer and 414 control women from the community matched by age, race, and area of residence.Main Outcome Measures.—Breast cancer stage at diagnosis.Results.—Of the 540 patients, 94 (17.4%) presented with TNM stage III or IV disease. The following demographic and socioeconomic factors were significant predictors of advanced stage: being African American (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.9-4.7); having low income (OR, 3.7; 95% CI, 2.1-6.5); never having been married (OR, 2.9; 95% CI, 1.4-5.9); having no private health insurance (OR, 2.5; 95% CI, 1.6-4.0); delaying seeing a physician because of money (OR, 1.6; 95% CI, 1.1-2.5); or lacking transportation (OR, 2.0; 95% CI, 1.2-3.6). Univariate analysis also revealed a large number of cultural beliefs to be significant predictors. Examples include the following beliefs: air causes a cancer to spread (OR, 2.8; 95% CI, 1.8-4.3); the devil can cause a person to get cancer (OR, 2.1; 95% CI, 1.2-3.5); women who have breast surgery are no longer attractive to men (OR, 1.9; 95% CI, 1.1-3.5); and chiropractic is an effective treatment for breast cancer (OR, 2.4; 95% CI, 1.4-4.4). When the demographic and socioeconomic variables were included in a multivariate logistic regression model, the OR for late stage among African Americans decreased to 1.8 (95% CI, 1.1-3.2) compared with 3.0 (95% CI, 1.9-4.7) for race alone. However, when the belief measures were included with the demographic and socioeconomic variables, the OR for late stage among African Americans decreased further to 1.2 (95% CI, 0.6-2.5).Conclusions.—Socioeconomic factors alone were not sufficient to explain the dramatic effect of race on breast cancer stage; however, socioeconomic variables in conjunction with cultural beliefs and attitudes could largely account for the observed effect.
Cystic fibrosis mice lacking Muc1 have reduced amounts of intestinal mucus.
Authors: R R Parmley, S J Gendler
Journal: Journal of Clinical Investigation (1998)

Normally a thin layer of mucus covers the surface of the gastrointestinal tract protecting the epithelial cells from their environment. In cystic fibrosis (CF), mucus accumulation is abnormally high, resulting in severe intestinal obstruction. The major structural components of mucus are large mucin glycoproteins. We determined specific mucin RNA and protein expression in the gastrointestinal tract of inbred CF transmembrane conductance regulator (CFTR) knockout (CF) mice and correlated expression with histological analyses of tissues. Mucins were detected histochemically using general carbohydrate stains and specific mucin antibodies. Mucin RNA levels were determined by reverse transcription-PCR. Comparisons were made between CF mice and control siblings, all maintained on a liquid diet after weaning. Analyses of the mucins Muc2, Muc3, and Muc5ac showed lower levels of RNA expression in the CF mice and similar levels of protein. Significantly, there was a sixfold increase in Muc1 RNA expression in the colon of the CF mouse and a moderate increase in Muc1 protein. Further, CF mice lacking Muc1 exhibited greatly diminished intestinal mucus obstruction when compared with Muc1- expressing CF mice and had better survival on solid food. We suggest that Muc1 plays an important role in the mucus obstructions observed in the gastrointestinal tract of the CFTR knockout mouse.
In micronodular cirrhosis, hepatocytes retain a normal C-25 hydroxylation capacity toward vitamin D3: A study using the rat carbon tetrachloride–induced cirrhotic model
Authors: Catherine Dubé, Sylvie Vallières, Chantal Éthier, Nawel Benbrahim, Chantale Tremblay, Marielle Gascon-Barré
Journal: Hepatology (1991)

To test further the competence of the cirrhotic liver to metabolize vitamin D3 at C-25, hepatocytes were isolated from controls and from CCl4-induced cirrhotic rat livers, as well as from partially hepatectomized rats. The transformation of D3 into 25-hydroxyvitamin D3 was studied in the presence of 107 hepatocytes at D3 concentrations of 20 nmol/L to 15.4 μmol/L. Histologically, micronodular cirrhosis was present in all CCl4-treated rats, whereas controls had normal livers; portal venous pressure (p < 0.008) and intrahepatic collagen content (p < 0.0001) were significantly increased in CCl4-treated rats, whereas no difference was found between the two groups in the total and ionized serum calcium, D3 metabolites, ALT, AST and alkaline phosphatase. Cytochrome P-450 was 0.27 ± 0.02 and 0.25 ± 0.02 nmol/106 hepatocytes in controls and cirrhotic rats (N.S.), and it significantly increased in both groups after phenobarbital or 3-methylcholanthrene administration (p < 0.0001). 25-Hydroxyvitamin D3 formation was best described by power law equations and varied between 0.02 ± 0.0004 and 29.57 ± 2.8 in controls, and 0.024 ± 0.0004 and 32.0 ± 7.0 pmol ± hr−1 ± 106 hepatocytes−1 in cirrhotic rats. No statistically significant difference was found in the slopes of the 25-hydroxyvitamin D3 formation, but the y-axis intercept was found to be lower in cirrhotic rats under basal resting conditions (p < 0.005). Inducers of the mixed function oxidases significantly increased 25-hydroxyvitamin D3 formation in controls as well as in cirrhotic rats (p < 0.005). Moreover, both groups were found to respond similarly to the addition of modulators of the enzyme such as the calcium ionophore A23187 and parathyroid hormone. Partial hepatectomy was also without effect on the activation of D3. Furthermore, the cell sequestration of D3 was also found to be unperturbed in hepatocytes obtained from either cirrhotic or partially hepatectomized livers. The data indicate that in well-compensated micronodular cirrhosis, the C-25 hydroxylation of D3 is generally intrinsically normal at the cellular level and that it also remains fully responsive to in vivo and in vitro modulators of its activity. (HEPATOLOGY 1991;13:489–499.)
Adenovirus-mediated gene transfer in the transplant setting. Part III. Variables affecting gene transfer in liver grafts Drazan KE, Wu L, Shen X, Bullington D, Jurim O, Busuttil RW, Shaked A. Transplantation 1995; 59: 670?673
Authors: Chandan Guha, Jayanta Roy Chowdhury
Journal: Hepatology (1995)
Pityriasis rubra pilaris—an autoradiographic study
Authors: W.A.D. GRIFFITHS, S. PIERIS
Journal: British Journal of Dermatology (1982)

A flash labelling index (FLI) was determined in involved skin and in an ‘uninvolved’ island in five patients with acute adult‐onset pityriasis rubra pilaris. Involved skin had a high FLI (9.65±1.3). The islands gave a FLI of 5.56±1.5. This was 70% greater than the normal controls (3.85±0.8) and the islands therefore cannot be regarded as normal skin. These values are less than those found in psoriasis.
Impact of Patient and Target-Vessel Characteristics on Arterial and Venous Bypass Graft Patency
Authors: Nimesh D. Desai, C. David Naylor, Alexander Kiss, Eric A. Cohen, Randi Feder-Elituv, Senri Miwa, Sam Radhakrishnan, James Dubbin, Leonard Schwartz, Stephen E. Fremes
Journal: Circulation (2007)

Background— The purpose of this investigation was to determine optimal patient and target-vessel characteristics to maximize arterial and venous graft patency on the basis of data from a large clinical trial. Methods and Results— Angiographic data on 440 radial artery grafts and 440 saphenous vein grafts were analyzed with methodology to account for within-patient clustering. Multivariable models that incorporated patient demographic, operative, anatomic, and postdischarge medical management were constructed to determine predictors of graft occlusion. Radial artery use was strongly protective against graft occlusion at 1 year after adjustment for all covariates, with a larger protective effect seen in women ( P =0.05 for a subgroup-by-treatment interaction). Among all grafts, diabetes and small target-vessel diameter were associated with an increased risk of graft occlusion, and grafting to a target vessel with more severe proximal stenosis was associated with a decreased risk of graft occlusion. With regard to gender, radial artery graft occlusion at 1 year occurred in similar proportions of men (8.6%) and women (5.3%, P =0.6), whereas, for saphenous vein grafts the comparable occlusion rates were 12.0% and 23.3% respectively ( P =0.02). A history of peripheral vascular disease was associated with an elevated risk of radial artery occlusion but was not associated with early vein graft occlusion ( P =0.02 for a subgroup-by-treatment interaction). Conclusions— Patients benefit from radial artery–coronary artery bypass conduits as opposed to saphenous vein conduits, and this effect is especially strong in women. Small target-vessel size adversely affected graft patency, and grafting to a target vessel with more severe proximal stenosis improved graft patency.
Sodium/calcium exchange modulates intracellular calcium overload during posthypoxic reoxygenation in mammalian working myocardium. Evidence from aequorin-loaded ferret ventricular muscles.
Authors: Y Kihara, S Sasayama, M Inoko, J P Morgan
Journal: Journal of Clinical Investigation (1994)

We tested the hypothesis that the intracellular Ca2+ overload of ventricular myocardium during the period of posthypoxic reoxygenation is mediated by transsarcolemmal Ca2+ influx via Na+/Ca2+ exchange. In aequorin-loaded, ferret right ventricular papillary muscles, blockers of the sarcolemmal and the sarcoplasmic reticulum Ca2+ channels, slowed the Cai2+ transient, producing a convex ascent during membrane depolarization, followed by a concave descent during repolarization. The magnitude of the Cai2+ transient was affected by changes in the membrane potential, Nai+, Nao+, and Cao2+, and was blocked by Ni2+, or dichlorbenzamil. The calculated Na+/Ca2+ exchange current was in the reverse mode (Ca2+ influx) during the ascending phase of the Cai2+ transient, and was abruptly switched to the forward mode (Ca2+ efflux) at repolarization, matching the time course of the Cai2+ transient. During hypoxic superfusion, the Cai2+ transient was abbreviated, which was associated with a shorter action potential duration. In contrast, immediately after reoxygenation, the Cai2+ transient increased to a level greater than that of the control, even though the action potential remained abbreviated. This is the first demonstration on a beat-to-beat basis that, during reoxygenation, Ca2+ influx via Na+/Ca2+ exchange is augmented and transports a significant amount of Ca2+ into the ventricular myocardial cell. The activation of the exchanger at the time of reoxygenation appears to be mediated by Nai+ accumulation, which occurs during hypoxia.
Bilirubin conjugate changes in the bile of gallbladders containing gallstones
Authors: Carl A. Goresky, Ellen R. Gordon, E. John Hinchey, Gerald M. Fried
Journal: Hepatology (1995)

Gallbladder bile was obtained at laparoscopic cholecystectomy from 31 patients with gallstones, and duodenal aspirates from 18 normal controls. Bile pigments (9 conjugates and unconjugated bilirubin) were analyzed by high-performance liquid chromatography. The average proportional composition of the bile pigments from the patients with gallstones was characteristically different from the controls. Whereas the average values for the principal conjugates in the controls were bilirubin diglucuronide 83.4%, bilirubin monoglucuronide 10.1%, bilirubin monoglucuronide monoglucoside 4.5%, and bilirubin monoglucuronide monoxyloside 1.0%, the corresponding values in the biles from the patients with gallstones were 66.3%, 20.6%, 6.5%, and 2.8%, respectively. Values from the more minor conjugates and unconjugated bilirubin were less than 2% in either data set. In samples obtained in 9 of the gallstone patients early and late in the procedure, no significant change was found. Over the spectrum of findings in the gallstone patients, as the proportion of bilirubin diglucuronide became smaller, that of bilirubin monoglucuronide increased substantially, whereas those of bilirubin monoglucuronide monoglucoside and bilirubin monoglucuronide monoxyloside increased to a small extent. The findings suggest that bilirubin diglucuronide hydrolysis occurs in the gallbladder bile of gallstone patients, with the production of bilirubin monoglucuronide, and that if further hydrolysis of bilirubin monoglucuronide occurs with the formation of unconjugated bilirubin, the latter does not ordinarily increase because it is being absorbed. Stasis with increased gallbladder residence time was likely present in some of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Quality measures need to be developed carefully to avoid being misinterpreted
Authors: Z. Kmietowicz
Journal: BMJ (2010)

To make quality indicators useful NHS providers need to define what they mean by quality, what they aim to gain by measuring it, how they are going to do this, and what they will do with the resulting data, says a health service think tank.

A discussion paper from the King’s Fund, says that measuring the quality and safety of health care is complex and challenging, and the measures used are often difficult to interpret. For example, league tables can be misinterpreted and mislead patients, distort …
Fluttering of the Mitral Valve in Aortic Insufficiency
Authors: FRED WINSBERG, GEORGE E. GABOR, JOSEPH G. HERNBERG, BARRY WEISS
Journal: Circulation (1970)

Thirty-five patients with clinical evidence of aortic insufficiency were studied by echocardiography. Eleven patients had characteristic diastolic fluttering of the mitral valve (30 to 40 Hz, maximal amplitude 4 mm). In five others the fluttering was classified as equivocal. In a control group of 500 echocardiograms in patients without evidence of aortic insufficiency, there were three examples of equivocal fluttering. Atrial fibrillation also produces diastolic fluttering but of slower frequency.