tbuckley/cabot-search huggingface dataset:
Evolution of Vitamin B6 (Pyridoxine) Metabolism by Gain and Loss of Genes
Authors: Tsuyoshi Tanaka, Yoshio Tateno, Takashi Gojobori
Journal: Molecular Biology and Evolution (2004)

Vitamin B(6) (VB6) functions as a cofactor of many diverse enzymes in amino acid metabolism. Three metabolic pathways for pyridoxal 5'-phosphate (PLP; the active form of VB6) are known: the de novo pathway, the salvage pathway, and the fungal type pathway. Most unicellular organisms and plants biosynthesize VB6 using one or two of these three biosynthetic pathways. However, animals such as insects and mammals do not possess any of the pathways and, thus, need to intake VB6 in their diet to survive. It is conceivable that breakdowns of these pathways occurred in the evolutionary lineages of insects and mammals, and one of the major reasons for this would be the loss of pertinent genes. We studied the evolution of VB6 biosynthesis from the view of the gain and loss of 10 pertinent genes in 122 species whose genome sequences were completely determined. The results revealed that each gene in the pathways was lost more than once in the entire evolutionary lineages of the 122 species. We also found the following three points regarding the evolution of PLP biosynthesis: (1) the breakdown of the PLP biosynthetic pathways occurred independently at least three times in animal lineages, (2) the de novo pathway was formed by the generation of pdxB in gamma-proteobacteria, and (3) the order of the gene loss in VB6 metabolism was conserved among different evolutionary lineages. These results suggest that the evolution of VB6 metabolism was subject to gains and frequent losses of related genes in the 122 species examined. This dynamic nature of the evolutionary changes must have been responsible for the breakdowns of the pathways, resulting in profound differentiation of heterotrophy among the species.
Effect of Catheter Sampling on the Shape of Indicator-Dilution Curves
Authors: C. W. SHEPPARD, MARSHALL P. JONES, BILLY LANIER COUCH
Journal: Circulation Research (1959)

The dispersion of a very short bolus of dye carried through a long cylindrical tube by a Newtonian fluid has been investigated theoretically and experimentally for two situations. In the first case a short bolus of uniform length and concentration is considered, representing a uniform amount of dye entering the tube per unit cross-sectional area independent of velocity of flow at a particular radius from the tube axis. In the second case concentration is uniform so that layers of fluid with greater velocity will carry in more dye than slower layers. Since velocities at the tube wall approach zero whereas velocities of axial dye are maximal, the axial fluid will contain greater amounts of dye per unit area. The implication of these principles to the dispersion of dye taken from deeply situated sites in the mammalian circulation through catheters of appreciable volumue is discussed.
Immunofluorescence identification of eosinophil granule major basic protein in the flame figures of Wells' syndrome
Authors: MARGOT S. PETERS, A.L. SCHROETER, G.J. GLEICH
Journal: British Journal of Dermatology (1983)

An indirect immunofluorescence assay using formalin-fixed paraffin-embedded skin was performed on six biopsies from four patients with eosinophilic cellulitis (Wells' syndrome) to determine the extracellular localization of eosinophil granule major basic protein (MBP). Serial sections from each biopsy were treated with either affinity chromatography-purified antihuman- MBP or staphylococcal protein A purified rabbit IgG (control material). There was striking extracellular fluorescence localized to flame figures, and intracellular staining of eosinophils in all sections treated with anti-MBP as compared with controls. The pattern of MBP extracellular staining corresponded to the configuration of each flame figure (as verified by counterstain of the same section with haematoxylin and eosin). These findings show that MBP can be used as a marker for determining eosinophil degranulation and, because MBP is localized to flame figures, they suggest that MBP may play a pathogenic role in Wells' syndrome.
Th1/Th2 lymphocyte polarization in asthma
Authors: G. Mazzarella, A. Bianco, E. Catena, R. De Palma, G. F. Abbate
Journal: Allergy (2000)

Asthma is a complex inflammatory disease of the lung characterized by variable airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Inflammation in asthma consists of airway infiltration by mast cells, lymphocytes, and eosinophils. There is accumulating evidence that CD4 + lymphocytes with a Th2‐cytokine pattern play a pivotal role in the pathogenesis of asthma. These cells orchestrate the recruitment and activation of the primary effector cells of the allergic response (mast cells and eosinophils), through the release of cytokines such as IL‐4, IL‐5, and IL‐13. Allergic inflammation is also implicated in airway epithelium changes, although the mechanisms by which inflammatory cells and, in particular, T cells interact with the epithelium are not completely clarified. This paper explores the role of T cells in the allergic inflammation of asthma.
Hypothalamic Control of Adrenocorticotropin Secretion: Advances since the Discovery of 41-Residue Corticotropin-Releasing Factor
Authors: FERENC A. ANTONI
Journal: Endocrine Reviews (1986)

IN THE 25 yrs after the first demonstration of CRF in hypothalamic tissue (1, 2), research on CRF progressed along two major lines of experimentation. In the context of a functional anatomical approach, researchers sought to elucidate the hypothalamic organization of neurons that produce CRF and control the secretion of ACTH (for reviews see Refs. 3–5). The second major trend was the quest for the isolation and chemical characterization of the hypothalamic CRF principle (for reviews see Refs. 6–8). It was the discovery of 41-amino acid residue CRF (CRF-41) by Vale and co-workers (9) which provided the missing link between the two major paths of investigation. Aided by decades of expertise accumulated in laboratories throughout the world, workers finally having the right stuff at hand rapidly established CRF-41 as a major physiological mediator of the hypothalamic control of ACTH secretion (for reviews see Refs. 10–12). However, it soon became evident that CRF-41 is not the sole hypothalamic neurohormone involved in the control of pituitary ACTH secretion (e.g. see Refs. 13–17). Thus, the second phase of CRF research, the post-CRF-41 era, had begun.
Pharmacokinetics of benzodiazepine antagonist Ro 15–1788 in cirrhotic patients with moderate or severe liver dysfunction
Authors: Gilles Pomier-Layrargues, J.-François Giguère, Joël Lavoie, Bernard Willems, Roger F. Butterworth
Journal: Hepatology (1989)

Ro 15-1788, a benzodiazepine antagonist, has been advocated as a new treatment for hepatic encephalopathy. This drug is extensively metabolized by the liver in normal subjects. In the present study, we examined Ro 15-1788 disposition in eight healthy controls (Group I), eight cirrhotic patients with moderately impaired liver function (Pugh score less than 10, Group II) and eight patients with severe liver dysfunction (Pugh score greater than 10, Group III). The subjects of each group were age and sex matched. After an intravenous infusion of 2 mg Ro 15-1788 over 5 min, blood samples were taken at fixed intervals up to 7 hr after the infusion. Plasma levels of the drug were determined by capillary gas chromatography. In controls, Ro 15-1788 had a high plasma clearance [16.3 +/- 2.6 ml per min per kg (mean +/- S.D.)], a short half-life (45.7 +/- 8.5 min), a large volume of distribution (0.62 +/- 0.09 liter per kg) and a low plasma protein binding (45 +/- 6%). Plasma clearance was reduced markedly in both groups of cirrhotic patients (-57 and -74%, respectively); the volume of distribution was unchanged in Group II and moderately increased in Group III (+37%). The elimination half-life was markedly prolonged in Groups II and III (+66 and +210%, respectively). Plasma clearance and Pugh score were highly correlated in cirrhotic patients (r = 0.830, p less than 0.001). The plasma protein binding of Ro 15-1788 was lower in cirrhotics, resulting in a significant increase in the free fraction of the drug (+16% in Group II; +44% in Group III).(ABSTRACT TRUNCATED AT 250 WORDS)
Abciximab Readministration
Authors: James E. Tcheng, Dean J. Kereiakes, A. Michael Lincoff, Barry S. George, Neal S. Kleiman, David C. Sane, Douglas B. Cines, Robert E. Jordan, Mary Ann Mascelli, Mary Ann Langrall, Lakshmi Damaraju, Allen Schantz, Mark B. Effron, Gregory A. Braden
Journal: Circulation (2001)

Background — Platelet glycoprotein IIb/IIIa blockade with abciximab (ReoPro) improves the clinical outcomes of percutaneous coronary intervention. This registry was conducted to characterize the effects of repeated administration of abciximab during intervention. Methods and Results — We recruited 500 consecutive patients at 22 centers in the United States who were receiving abciximab for at least a second time during percutaneous coronary intervention. Safety was measured as the incidence of hypersensitivity reactions, major bleeding, and thrombocytopenia. Efficacy was assessed as event-free clinical success. Human antichimeric antibody (HACA) responses were also characterized. There were no cases of hypersensitivity (95% upper confidence bound, 0.3%), major bleeding, or death. Clinical success was 94.4%. Thrombocytopenia occurred in 23 patients (4.6%; 95% CI, 2.8% to 6.4%), including 12 (2.4%; 95% CI, 1.1% to 3.7%) who developed profound thrombocytopenia (&lt;20×10 9 cells/L). In 2 patients (0.4%), profound thrombocytopenia did not develop until after hospital discharge; in 4 (0.8%), profound thrombocytopenia recurred despite platelet transfusion. Before a first readministration, a positive HACA titer was present in 22 of 454 patients (4.8%); after a first readministration, an additional 82 of 432 (19.0%) became HACA-positive. HACA did not neutralize the in vitro inhibition of platelet aggregation by abciximab or correlate with clinical events. Conclusions — The results, including overall rates of thrombocytopenia, were consistent with randomized clinical trials of first abciximab treatment. However, there was a shift from mild to profound thrombocytopenia, and cases of delayed presentation and of recurrent thrombocytopenia were seen. These findings suggest that indications and guidelines for first-time use apply to retreatment, particularly the systematic monitoring for thrombocytopenia.
HDAC Inhibition Suppresses Primary Immune Responses, Enhances Secondary Immune Responses, and Abrogates Autoimmunity During Tumor Immunotherapy
Authors: Byram W Bridle, Lan Chen, Chantal G Lemay, Jean-Simon Diallo, Jonathan Pol, Andrew Nguyen, Alfredo Capretta, Rongqiao He, Jonathan L Bramson, John C Bell, Brian D Lichty, Yonghong Wan
Journal: Molecular Therapy (2013)

Histone deacetylase inhibitors (HDACi) can modulate innate antiviral responses and render tumors more susceptible to oncolytic viruses (OVs); however, their effects on adaptive immunity in this context are largely unknown. Our present study reveals an unexpected property of the HDACi MS-275 that enhances viral vector-induced lymphopenia leading to selective depletion of bystander lymphocytes and regulatory T cells while allowing expansion of antigen-specific secondary responses. Coadministration of vaccine plus drug during the boosting phase focuses the immune response on the tumor by suppressing the primary immune response against the vaccine vector and enhancing the secondary response against the tumor antigen. Furthermore, improvement of T cell functionality was evident suggesting that MS-275 can orchestrate a complex array of effects that synergize immunotherapy and viral oncolysis. Surprisingly, while MS-275 dramatically enhanced efficacy, it suppressed autoimmune pathology, profoundly improving the therapeutic index. Histone deacetylase inhibitors (HDACi) can modulate innate antiviral responses and render tumors more susceptible to oncolytic viruses (OVs); however, their effects on adaptive immunity in this context are largely unknown. Our present study reveals an unexpected property of the HDACi MS-275 that enhances viral vector-induced lymphopenia leading to selective depletion of bystander lymphocytes and regulatory T cells while allowing expansion of antigen-specific secondary responses. Coadministration of vaccine plus drug during the boosting phase focuses the immune response on the tumor by suppressing the primary immune response against the vaccine vector and enhancing the secondary response against the tumor antigen. Furthermore, improvement of T cell functionality was evident suggesting that MS-275 can orchestrate a complex array of effects that synergize immunotherapy and viral oncolysis. Surprisingly, while MS-275 dramatically enhanced efficacy, it suppressed autoimmune pathology, profoundly improving the therapeutic index.
Novel Platelet Inhibitors
Authors: Joel S. Bennett
Journal: Annual Review of Medicine (2001)

▪ Abstract Platelet-inhibitory drugs are of proven benefit to individuals who suffer from atherosclerotic cardiovascular disease. Despite substantial effort to identify more potent platelet-inhibitory agents, aspirin, an irreversible inhibitor of platelet cyclooxygenase activity, remains the standard against which other drugs are judged. Drugs that appear to be at least as efficacious as aspirin in specific clinical settings include the thienopyridines ticlopidine and clopidogrel, specific inhibitors of ADP-stimulated platelet function, and the phosphodiesterase 3 inhibitor cilostazol. Ligand binding to the platelet integrin αIIbβ3 (GPIIb-IIIa), a prerequisite for platelet thrombus formation, has been a prominent target for drug development. Currently, three types of αIIbβ3 antagonists are available: the monoclonal antibody Fab fragment abciximab, cyclic peptides based on the Arg-Gly-Asp (RGD) or related amino acid motifs, and RGD-based peptidomimetics. The efficacy of each type of αIIbβ3 antagonist in the setting of acute coronary artery disease has been confirmed in multicenter clinical trials.
Structural forms of the human amylase locus and their relationships to SNPs, haplotypes and obesity
Authors: Christina L Usher, Robert E Handsaker, Tõnu Esko, Marcus A Tuke, Michael N Weedon, Alex R Hastie, Han Cao, Jennifer E Moon, Seva Kashin, Christian Fuchsberger, Andres Metspalu, Carlos N Pato, Michele T Pato, Mark I McCarthy, Michael Boehnke, David M Altshuler, Timothy M Frayling, Joel N Hirschhorn, Steven A McCarroll
Journal: Nature Genetics (2015)
Clinical Model for Management of Pulmonary Embolism
Authors: John F. Whitney
Journal: Annals of Internal Medicine (1999)

Letters21 September 1999Clinical Model for Management of Pulmonary EmbolismJohn F. Whitney, MDJohn F. Whitney, MDAlbany Medical College; Albany, NY 12208 (Whitney)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-131-6-199909210-00017 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITORI disagree with Ginsberg and colleagues (1) that their study supports the use of a d-dimer assay in the routine evaluation of suspected pulmonary embolism.The greatest challenge in pulmonary embolism diagnosis arises when clinical circumstances are unclear and a decision must be made to proceed to a definitive diagnostic test (that is, pulmonary angiography). The d-dimer assay they used could not detect thromboembolism in 5 of 24 (21%) patients with low pretest probability and in 20 of 81 (25%) patients with moderate pretest probability (Table 1 of the authors' article). These patients would have been sent ...Reference1. Ginsberg JS, Wells PS, Kearon C, Anderson D, Crowther M, Weitz JI, et al . Sensitivity and specificity of a rapid whole-blood assay for d-dimer in the diagnosis of pulmonary embolism. Ann Intern Med. 1998;129:1006-11. LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Albany Medical College; Albany, NY 12208 (Whitney) PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoUse of a Clinical Model for Safe Management of Patients with Suspected Pulmonary Embolism Philip S. Wells , Jeffrey S. Ginsberg , David R. Anderson , Clive Kearon , Michael Gent , Alexander G. Turpie , Janis Bormanis , Jeffrey Weitz , Michael Chamberlain , Dennis Bowie , David Barnes , and Jack Hirsh Clinical Model for Management of Pulmonary Embolism Stephen J. Jay Clinical Model for Management of Pulmonary Embolism Paul Egermayer Clinical Model for Management of Pulmonary Embolism Philip Wells , David Anderson , and Jeffrey Ginsberg Clinical Model for Management of Pulmonary Embolism Jeffrey Pickard Metrics 21 September 1999Volume 131, Issue 6Page: 474KeywordsAngiographyD-dimerFallsPulmonary embolismPulmonary hypertensionThromboembolismVentilation perfusion Issue Published: 21 September 1999 Copyright & PermissionsCopyright © 1999 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Predicting Anthracycline Benefit: <i>TOP2A</i> and CEP17—Not Only but Also
Authors: John M.S. Bartlett, Christopher C. McConkey, Alison F. Munro, Christine Desmedt, Janet A. Dunn, Denis P. Larsimont, Frances P. O'Malley, David A. Cameron, Helena M. Earl, Christopher J. Poole, Lois E. Shepherd, Fatima Cardoso, Maj-Britt Jensen, Carlos Caldas, Christopher J. Twelves, Daniel W. Rea, Bent Ejlertsen, Angelo Di Leo, Kathleen I. Pritchard
Journal: Journal of Clinical Oncology (2015)

Purpose Evidence supporting the clinical utility of predictive biomarkers of anthracycline activity is weak, with a recent meta-analysis failing to provide strong evidence for either HER2 or TOP2A. Having previously shown that duplication of chromosome 17 pericentromeric alpha satellite as measured with a centromere enumeration probe (CEP17) predicted sensitivity to anthracyclines, we report here an individual patient–level pooled analysis of data from five trials comparing anthracycline-based chemotherapy with CMF (cyclophosphamide, methotrexate, and fluorouracil) as adjuvant chemotherapy for early breast cancer. Patients and Methods Fluorescent in situ hybridization for CEP17, HER2, and TOP2A was performed in three laboratories on samples from 3,846 of 4,864 eligible patients from five trials evaluating anthracycline-containing chemotherapy versus CMF. Methodologic differences did not affect HER2-to-CEP17 ratios but necessitated different definitions for CEP17 duplication: &gt; 1.86 observed copies per cell for BR9601, NEAT, Belgian, and DBCG89D trials and &gt; 2.25 for the MA.5 trial. Results Fluorescent in situ hybridization data were available in 89.3% (HER2), 83.9% (CEP17), and 80.6% (TOP2A) of 3,846 patient cases with available tissue. Both CEP17and TOP2A treatment-by-marker interactions remained significant in adjusted analyses for recurrence-free and overall survival, whereas HER2 did not. A combined CEP17 and TOP2A–adjusted model predicted anthracycline benefit across all five trials for both recurrence-free (hazard ratio, 0.64; 95% CI, 0.51 to 0.82; P = .001) and overall survival (hazard ratio, 0.66; 95% CI, 0.51 to 0.85; P = .005). Conclusion This prospectively planned individual-patient pooled analysis of patient cases from five adjuvant trials confirms that patients whose tumors harbor either CEP17 duplication or TOP2A aberrations, but not HER2 amplification, benefit from adjuvant anthracycline chemotherapy.
The immunodeficient scid mouse as a model for human lymphatic filariasis.
Authors: F K Nelson, D L Greiner, L D Shultz, T V Rajan
Journal: The Journal of Experimental Medicine (1991)

The C.B.-17-scid/scid mouse (hereafter referred to as the scid mouse) is homozygous for a recessive mutation at a locus that influences the assembly of intact immunoglobulin and T cell receptor genes. Therefore, scid mice cannot generate functional B or T lymphocytes, are profoundly immunodeficient, and have been reported to be receptive to reconstitution with human immune cells. In the present study, we injected scid mice with infective larvae of the human filarial parasite Brugia malayi. Within 6-10 wk after subcutaneous injection of infective L3 larvae, both male and female worms were observed in various stages of development in 90% of the mice. In animals tested 8 weeks or more after infection, microfilariae were detected in the blood or peritoneal cavity of 52% of the mice examined. Adult worms were observed in the lymphatics of the infected scid mice, where their presence was associated with lymphangitis and lymphangiectasia. These results suggest that the scid mouse model of lymphatic filariasis may be important in investigation of the interaction of the murine, and possibly the human, immune system with the lymphatic filarial parasite.
EVIDENCE THAT THE BONE RESORPTION-STIMULATING FACTOR PRODUCED BY MOUSE FIBROSARCOMA CELLS IS PROSTAGLANDIN E2
Authors: Armen H. Tashjian, Edward F. Voelkel, Lawrence Levine, Paul Goldhaber
Journal: The Journal of Experimental Medicine (1972)

A transplantable mouse fibrosarcoma, HSDM(1), produces a potent bone resorption-stimulating factor. The factor can be extracted from the tumor tissue and harvested from the medium of clonal strains of HSDM(1) tumor cells growing in monolayer culture. It has several chemical and biological properties of a prostaglandin. Using radioimmunoassay techniques, we have shown that HSDM(1) cells synthesize and secrete large quantities of prostaglandin E(2) (PGE(2)). The specific bone resorption-stimulating activity of the HSDM(1) factor extracted from the tumor is high and approximately equal to that of PGE(2) as measured in a bone tissue culture system in vitro. Indomethacin, a potent inhibitor of PGE(2) synthesis in HSDM(1) cells, also inhibits production by the cells of the bone resorption-stimulating factor, and has no detectable nonspecific effects on the bone culture assay system. Mice bearing the HSDM(1) tumor have higher levels of both calcium and PGE(2) in serum than control mice. We conclude that PGE(2) is the bone resorption-stimulating factor produced by HSDM(1) tumor cells, and that secretion of PGE(2) by the tumor in vivo accounts for the relative hypercalcemia observed in tumor-bearing animals. The HSDM(1) tumor cell system constitutes a new model for studying the pathogenesis of hypercalcemia associated with certain malignant tumors.
Sentinel-Node Biopsy or Nodal Observation in Melanoma
Authors: Donald L. Morton, John F. Thompson, Alistair J. Cochran, Nicola Mozzillo, Robert Elashoff, Richard Essner, Omgo E. Nieweg, Daniel F. Roses, Harald J. Hoekstra, Constantine P. Karakousis, Douglas S. Reintgen, Brendon J. Coventry, Edwin C. Glass, He-Jing Wang
Journal: New England Journal of Medicine (2006)

We evaluated the contribution of sentinel-node biopsy to outcomes in patients with newly diagnosed melanoma.