tbuckley/cabot-search huggingface dataset:
Vessel Wall–Embedded Dendritic Cells Induce T-Cell Autoreactivity and Initiate Vascular Inflammation
Authors: Ji W. Han, Kazunori Shimada, Wei Ma-Krupa, Tiffany L. Johnson, Robert M. Nerem, Jörg J. Goronzy, Cornelia M. Weyand
Journal: Circulation Research (2008)

Human medium-sized and large arteries are targeted by inflammation with innate and adaptive immune responses occurring within the unique microspace of the vessel wall. How 3D spatial arrangements influence immune recognition and cellular response thresholds and which cell populations sense immunoactivating ligands and function as antigen-presenting cells are incompletely understood. To mimic the 3D context of human arteries, bioartificial arteries were engineered from collagen type I matrix, human vascular smooth muscle cells (VSMCs), and human endothelial cells and populated with cells implicated in antigen presentation and T-cell stimulation, including monocytes, macrophages, and myeloid dendritic cells (DCs). Responsiveness of wall-embedded antigen-presenting cells was probed with the Toll-like receptor ligand lipopolysaccharide, and inflammation was initiated by adding autologous CD4(+) T cells. DCs colonized the outermost VSMC layer, recapitulating their positioning at the media-adventitia border of normal arteries. Wall-embedded DCs responded to the microbial product lipopolysaccharide by entering the maturation program and upregulating the costimulatory ligand CD86. Activated DCs effectively stimulated autologous CD4 T cells, which produced the proinflammatory cytokine interferon-gamma and infiltrated deeply into the VSMC layer, causing matrix damage. Lipopolysaccharide-triggered macrophages were significantly less efficacious in recruiting T cells and promoting T-cell stimulation. CD14(+) monocytes, even when preactivated, failed to support initial steps of vascular wall inflammation. Innate immune cells, including monocytes, macrophages, and DCs, display differential functions in the vessel wall. DCs are superior in sensing pathogen-derived motifs and are highly efficient in breaking T-cell tolerance, guiding T cells toward proinflammatory and tissue-invasive behavior.
Gynecologic Oncology or Medical Oncology: What's in a Name?
Authors: Stephen A. Cannistra
Journal: Journal of Clinical Oncology (2007)

Patients with advanced epithelial ovarian cancer generally require postoperative platinum-based chemotherapy in an attempt to prolong both disease-free and overall survival. Unlike most other areas of oncology, where chemotherapy has traditionally been administered by medical oncologists, postoperative chemotherapy for ovarian cancer may also be administered by gynecologic oncologists, who receive chemotherapy training as part of a surgically oriented fellowship. Nonetheless, the division of labor between gynecologic oncologists primarily trained to operate and medical oncologists trained in chemotherapy decision making, dosing, and adverse effect management, seems natural to many physicians involved in the care of patients with ovarian cancer. Physicians often work as a team, with the gynecologic oncologist managing the surgical aspects of this disease and the medical oncologist being responsible for chemotherapy administration. However, this paradigm is not universal, and the model of the gynecologic oncologist delivering both surgical as well as chemotherapeutic care is active in many parts of the United States and elsewhere in the world. In this issue of the Journal, Silber et al use the Surveillance, Epidemiology, and End Results (SEER)-Medicare data to assess survival, chemotherapy usage, and adverse effects for patients with epithelial ovarian cancer who received chemotherapy under the care of either gynecologic oncologists or medical oncologists. 1 The authors hypothesized that the survival of patients treated by medical oncologists would be superior in view of their training. Instead, Silber et al found that survival was equivalent between these two groups of subspecialists when adjusting for stage, age, histology, ethnicity, medical comorbidity, and the initial operating physician (usually a gynecologic oncologist). However, patients treated by medical oncologists tended to receive chemotherapy more frequently and have more reported adverse effects than those treated by gynecologic oncologists. The authors conclude that perhaps “medical oncologists believed in treatment intensity more than gynecologic oncologists,” and “that gynecologic oncologists had better intuition regarding when to reduce intensity in favor of quality of life.” 1 Regarding this last point, it should be noted that quality of life was not assessed as part of this study, making it impossible to draw conclusions about the effects of treatment frequency on this outcome.
CF Gene and Cystic Fibrosis Transmembrane Conductance Regulator Expression in Autosomal Dominant Polycystic Kidney Disease
Authors: ALEXANDRE PERSU, OLIVIER DEVUYST, NATHALIE LANNOY, ROLAND MATERNE, GODELA BROSNAHAN, PATRICIA A. GABOW, YVES PIRSON, CHRISTINE VERELLEN-DUMOULIN
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Disease-modifying genes might participate in the significant intrafamilial variability of the renal phenotype in autosomal dominant polycystic kidney disease (ADPKD). Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is a chloride channel that promotes intracystic fluid secretion, and thus cyst progression, in ADPKD. The hypothesis that mutations of the CF gene, which encodes CFTR, might be associated with a milder renal phenotype in ADPKD was tested. A series of 117 unrelated ADPKD probands and 136 unaffected control subjects were screened for the 12 most common mutations and the frequency of the alleles of the intron 8 polymorphic Tn locus of CF. The prevalence of CF mutations was not significantly different in the ADPKD (1.7%, n = 2) and control (3.7%, n = 5) groups. The CF mutation was ΔF508 in all cases, except for one control subject (1717-1G A). The frequencies of the 5T, 7T, and 9T intron 8 alleles were also similar in the ADPKD and control groups. Two additional patients with ADPKD and the ΔF508 mutation were detected in the families of the two probands with CF mutations. Kidney volumes and renal function levels were similar for these four patients with ADPKD and ΔF508 CFTR (heterozygous for three and homozygous for one) and for control patients with ADPKD collected in the University of Colorado Health Sciences Center database. The absence of a renal protective effect of the homozygous ΔF508 mutation might be related to the lack of a renal phenotype in CF and the variable, tissue-specific expression of ΔF508 CFTR. Immunohistochemical analysis of a kidney from the patient with ADPKD who was homozygous for the ΔF508 mutation substantiated that hypothesis, because CFTR expression was detected in 75% of cysts (compared with <50% in control ADPKD kidneys) and at least partly in the apical membrane area of cyst-lining cells. These data do not exclude a potential protective role of some CFTR mutations in ADPKD but suggest that it might be related to the nature of the mutation and renal expression of the mutated CFTR.
The Importance of Reporting Patient Recruitment Details in Phase III Trials
Authors: James R. Wright, Sarah Bouma, Ian Dayes, Jonathan Sussman, Marko R. Simunovic, Mark N. Levine, Tim J. Whelan
Journal: Journal of Clinical Oncology (2006)

James R. Wright, Juravinski Cancer Centre at Hamilton Health Sciences, and Department of Medicine, McMaster University, Hamilton, ON, Canada Sarah Bouma, Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, ON, Canada Ian Dayes and Jonathan Sussman, Juravinski Cancer Centre at Hamilton Health Sciences, and Department of Medicine, McMaster University, Hamilton, ON, Canada Marko R. Simunovic, Juravinski Cancer Centre at Hamilton Health Sciences, and Department of Surgery, McMaster University, Hamilton, ON, Canada Mark N. Levine, Juravinski Cancer Centre at Hamilton Health Sciences, and Departments of Medicine and Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada Tim J. Whelan, Juravinski Cancer Centre at Hamilton Health Sciences, and Department of Medicine, McMaster University, Hamilton, ON, Canada
Identification of the Fenretinide Metabolite 4-Oxo-Fenretinide Present in Human Plasma and Formed in Human Ovarian Carcinoma Cells through Induction of Cytochrome P450 26A1
Authors: Maria Grazia Villani, Valentina Appierto, Elena Cavadini, Manuela Valsecchi, Sandro Sonnino, Robert W. Curley, Franca Formelli
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The synthetic retinoid fenretinide (4-HPR) exhibits preventive and therapeutic activity against ovarian tumors. An unidentified polar metabolite was previously found in 4-HPR-treated subjects and in A2780 human ovarian carcinoma cells continuously treated with 4-HPR (A2780/HPR). The metabolite and the enzyme involved in its formation in tumor cells are herein identified. Experimental Design: The metabolite was identified by mass spectrometry in A2780/HPR cell extracts and in plasma from 11 women participating in a phase III trial and treated with 200 mg/d 4-HPR for 5 years. The expression of proteins involved in retinoid metabolism and transport, cytochrome P450 26A1 (CYP26A1), cellular retinol-binding protein I (CRBP-I), and cellular retinoic acid-binding protein I and II (CRABP-I, CRABP-II) were evaluated in tumor cells by reverse transcription-PCR and Western blot analyses. Overexpression of CYP26A1 and retinoic acid receptors (RARs) in A2780 cells were obtained by cDNAs transfection. Results: The polar metabolite was 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) i.e., an oxidized form of 4-HPR with modification in position 4 of the cyclohexene ring. 4-oxo-4-HPR plasma levels were slightly lower (0.52 ± 0.17 μmol/L) than those of the parent drug (0.84 ± 0.53 μmol/L) and of the already identified metabolite N-(4-methoxyphenyl)retinamide (1.13 ± 0.85 μmol/L). In A2780/HPR cells continuously treated with 4-HPR and producing 4-oxo-4-HPR, CYP26A1 and CRBP-I were markedly up-regulated compared with A2780 untreated cells. In A2780 cells, not producing 4-oxo-4-HPR, overexpression of CYP26A1 caused formation of 4-oxo-4-HPR, which was associated with no change in 4-HPR sensitivity. Moreover, the addition of 4-oxo-4-HPR to A2780 cells inhibited cell proliferation. Elevated levels of CYP26A1 protein and metabolism of 4-HPR to 4-oxo-4-HPR were found in A2780 cells transfected with RARβ and to a lesser extent in those transfected with RARγ. Conclusions: A new metabolite of 4-HPR, 4-oxo-4-HPR, present in human plasma and in tumor cells, has been identified. The formation of this biologically active metabolite in tumor cells was due to CYP26A1 induction and was influenced by RAR expression. Moreover evidence was provided that 4-HPR up-modulates the expression of CRBP-I transcript, which is lost during ovarian carcinogenesis.
Use of B-Type Natriuretic Peptide in the Evaluation and Management of Acute Dyspnea
Authors: Christian Mueller, André Scholer, Kirsten Laule-Kilian, Benedict Martina, Christian Schindler, Peter Buser, Matthias Pfisterer, André P. Perruchoud
Journal: New England Journal of Medicine (2004)

B-type natriuretic peptide levels are higher in patients with congestive heart failure than in patients with dyspnea from other causes.
Traumatic tear of tibialis anterior during a Gaelic football game: a case report
Authors: M Constantinou, A Wilson
Journal: British Journal of Sports Medicine (2004)

Reports of traumatic injury to the anterior lower leg muscles are scarce, with only a handful of reports of traumatic injury to the tibialis anterior. A database search of Medline, Cinhal, and Sports Discus only revealed three such cases, and they did not result from a direct sporting injury. This report documents the case of a traumatic rupture of tibialis anterior muscle in a young female Gaelic football player. It details the surgical repair and management of tibialis anterior muscle and the physiotherapy rehabilitation to full function.
Sulfhydryl Groups of the Erythrocyte Membrane and their Relation to Glycolysis and Drug-Induced Hemolytic Anemia
Authors: Alvin Zipursky, Marlene Stephens, Elizabeth J. Brown, Per Larsen
Journal: Journal of Clinical Investigation (1974)

Hemolytic anemia caused by oxidative drugs is thought to result from the oxidation of intracellular and membrane sulfhydryl groups of the erythrocyte. This process is more likely to occur in those erythrocytes in which the intracellular mechanism for reduction of disulfides is abnormal (e.g., glucose-6-phosphate dehydrogenase deficiency). If a membrane sulfhydryl group is critical in the pathogenesis of druginduced hemolytic anemia, it follows that this specific group must be dependent on intracellular reductive mechanisms for maintenance of the reduced state. This report describes a sulfhydryl group(s), involved in membrane structure, which is (are) dependent on intracellular metabolism for maintenance of the reduced state. It is postulated that this metabolically dependent membrane sulfhydryl group may play a role in the pathogenesis of drug-induced hemolytic anemia. Membrane sulfhydryl groups were studied by observing the effect of sulfhydryl blocking agents, e.g., N-ethyl-maleimide (NEM), on the recovery of erythrocyte ghosts after osmotic lysis. It was shown that NEM interfered with ghost recovery by reacting with membrane sulfhydryl groups. The concentration of NEM (as determined by [(14)C] NEM binding) necessary to cause this effect was lower than that necessary to produce changes in osmotic fragility or cation permeability, or to cause Heinz body formation. In the absence of glucose, these sulfhydryl groups became disulfides, but could be returned to the reduced state by restoring glycolysis or by adding dithiothreitol. Phenylhydrazine hemolytic anemia was induced in pigs, and membrane changes of the type described above occurred early in the pathogenesis of the disease.
Protein Biomarker Identification in the CSF of Patients With CNS Lymphoma
Authors: Sushmita Roy, S. Andrew Josephson, Jane Fridlyand, Jon Karch, Cigall Kadoch, Juliana Karrim, Lloyd Damon, Patrick Treseler, Sandeep Kunwar, Marc A. Shuman, Ted Jones, Christopher H. Becker, Howard Schulman, James L. Rubenstein
Journal: Journal of Clinical Oncology (2007)

Purpose Elucidation of the CSF proteome may yield insights into the pathogenesis of CNS disease. We tested the hypothesis that individual CSF proteins distinguish CNS lymphoma from benign focal brain lesions. Methods We used a liquid chromatography/mass spectrometry–based method to differentially quantify and identify several hundred CSF proteins in CNS lymphoma and control patients. We used enzyme-linked immunosorbent assay (ELISA) to confirm one of these markers in an additional validation set of 101 cases. Results Approximately 80 CSF proteins were identified and found to be present at significantly different concentrations, both higher and lower, in training and test studies, which were highly concordant. To further validate these observations, we defined in detail the expression of one of these candidate biomarkers, antithrombin III (ATIII). ATIII RNA transcripts were identified within CNS lymphomas, and ATIII protein was localized selectively to tumor neovasculature. Determination of ATIII concentration by ELISA was significantly more accurate (&gt; 75% sensitivity; &gt; 98% specificity) than cytology in the identification of cancer. Measurement of CSF ATIII levels was found to potentially enhance the ability to diagnose and predict outcome. Conclusion Our findings demonstrate for the first time that proteomic analysis of CSF yields individual biomarkers with greater sensitivity in the identification of cancer than does CSF cytology. We propose that the discovery of CSF protein biomarkers will facilitate early and noninvasive diagnosis in patients with lesions not amenable to brain biopsy, as well as provide improved surrogates of prognosis and treatment response in CNS lymphoma and brain metastasis.
Ligand-dependent dynamics of retinoic acid receptor binding during early neurogenesis
Authors: Shaun Mahony, Esteban O Mazzoni, Scott McCuine, Richard A Young, Hynek Wichterle, David K Gifford
Journal: Genome biology (2011)

Among its many roles in development, retinoic acid determines the anterior-posterior identity of differentiating motor neurons by activating retinoic acid receptor (RAR)-mediated transcription. RAR is thought to bind the genome constitutively, and only induce transcription in the presence of the retinoid ligand. However, little is known about where RAR binds to the genome or how it selects target sites.We tested the constitutive RAR binding model using the retinoic acid-driven differentiation of mouse embryonic stem cells into differentiated motor neurons. We find that retinoic acid treatment results in widespread changes in RAR genomic binding, including novel binding to genes directly responsible for anterior-posterior specification, as well as the subsequent recruitment of the basal polymerase machinery. Finally, we discovered that the binding of transcription factors at the embryonic stem cell stage can accurately predict where in the genome RAR binds after initial differentiation.We have characterized a ligand-dependent shift in RAR genomic occupancy at the initiation of neurogenesis. Our data also suggest that enhancers active in pluripotent embryonic stem cells may be preselecting regions that will be activated by RAR during neuronal differentiation.
Matrix-assisted laser desorption ionization time-of-flight mass spectrometry: revolutionizing clinical laboratory diagnosis of mould infections
Authors: M. Gautier, S. Ranque, A.-C. Normand, P. Becker, A. Packeu, C. Cassagne, C. L'Ollivier, M. Hendrickx, R. Piarroux
Journal: Clinical Microbiology and Infection (2014)
Phase I Study of the Sequential Combination of Interleukin-12 and Interferon Alfa-2b in Advanced Cancer: Evidence for Modulation of Interferon Signaling Pathways by Interleukin-12
Authors: Charles F. Eisenbeis, Gregory B. Lesinski, Mirela Anghelina, Robin Parihar, Daniel Valentino, Jing Liu, Padma Nadella, Poongothai Sundaram, Donn C. Young, Mario Sznol, Michael J. Walker, William E. Carson
Journal: Journal of Clinical Oncology (2005)

To evaluate the safety of sequentially administered recombinant (r) human (h) interleukin-12 (IL-12) and interferon alfa-2b (IFN-alpha-2b) in patients with advanced cancer and to determine the effects of endogenously produced IFN-gamma on Janus kinase-signal transducer and activator of transcription (Jak-STAT) signal transduction in patient peripheral-blood mononuclear cells (PBMCs).Forty-nine patients with metastatic cancer received rhIL-12 on day 1 and IFN-alpha-2b on days 2 to 6 of either a 14-day (n = 43) or a 7-day treatment cycle (n = 6). rhIL-12 was initially administered subcutaneously at a dose of 100 ng/kg, whereas IFN-alpha-2b was escalated from 1 to 10 million units (MU) in cohorts of three patients (1, 3, 5, 7, or 10 MU). rhIL-12 was subsequently administered intravenously (IV) in escalating doses (100 to 500 ng/kg) to achieve greater IFN-gamma production. Peripheral blood was drawn for measurement of plasma IFN-gamma and the induction of Jak-STAT signal transduction in PBMCs.No IL-12-or IFN-alpha-related dose-limiting toxicities were observed. There were no responses in 41 assessable patients. Five patients exhibited stable disease lasting 6 months or longer while on therapy. Optimal induction of IFN-gamma by IL-12 occurred after an IV dose of 250 ng/kg. Patient PBMCs exhibited increased levels of STAT1 after IL-12 administration. The peak level of IFN-gamma achieved with IL-12 therapy correlated with the peak level of intracellular STAT1 in patient PBMCs (r = 0.38, P = .021).The combination of rhIL-12 and IFN-alpha-2b can be administered sequentially with minimal toxicity. IV administration of rhIL-12 modulates IFN-alpha-induced Jak-STAT signal transduction in patient PBMCs.
STRUCTURAL STUDIES OF HUMAN 7S γ-GLOBULIN (G IMMUNOGLOBULIN)
Authors: E. C. Franklin
Journal: The Journal of Experimental Medicine (1964)

1. Detailed physical, chemical, and immunologic studies of a protein closely related to the Fc fragment and heavy chain of G immunoglobulin (IgG), and elaborated by a subject with a lymphoproliferative disorder are presented. 2. The protein, which has a molecular weight of 51,000, was cleaved into two half molecules by reduction and alkylation. 3. The protein has few if any of the antigenic determinants of the antigen-binding (Fab) papain fragment of IgG, and has a striking similarity in its antigenic properties to the Fc fragment. 4. Fingerprint patterns resemble those of the crystallizable (Fc) fragment, and lack several peptides found in the heavy chain. 5. These findings suggest that the Fc fragment may be a real structural unit of IgG, and raise the possibility of the existence of three different types of polypeptide chains in G immunoglobulin.
Action of Bradykinin on Human Pulmonary Circulation
Authors: FLAVIO M. DE FREITAS, EDUARDO Z. FARACO, DECIO F. DE AZEVEDO, ISAAC LEWIN
Journal: Circulation (1966)

Twenty-one patients with pulmonary hypertension secondary to rheumatic mitral valve disease were submitted to right and left heart catheterization and received a continuous intravenous infusion of synthetic bradykinin (average dose, 0.98 µg/kg/min). The drug elicited an appreciable fall of the systemic vascular resistance simultaneously with a decrease of the mean systemic arterial pressure and an increase of the cardiac output in all cases. The rise in cardiac output derived mainly from an increase in heart rate, since the modifications of the stroke volume were generally of low magnitude. In the pulmonary circulation, the increase in blood flow was coincident with a rise of the mean arterial and venous (left atrial) pressures in 19 and all patients, respectively. The pulmonary vascular resistance fell in 19 patients, but no appreciable modifications were noted in pulmonary blood volume. The changes in the lesser circulation were interpreted as expressing secondary effects, either mechanical or reflex, consequent to the action of bradykinin on the systemic vessels and heart rather than a direct effect of the drug on the pulmonary vessels.
The incidence, risk factors, and outcome of transfusion-related acute lung injury in a cohort of cardiac surgery patients: a prospective nested case-control study
Authors: Alexander P. J. Vlaar, Jorrit J. Hofstra, Rogier M. Determann, Denise P. Veelo, Frederique Paulus, Wim Kulik, Johanna Korevaar, Bas A. de Mol, Marianne M. W. Koopman, Leendert Porcelijn, Jan M. Binnekade, Margreeth B. Vroom, Marcus J. Schultz, Nicole P. Juffermans
Journal: Blood (2011)
Isoniazid Toxicity
Authors: Richard B. Byrd
Journal: JAMA (1972)

The toxicity of isoniazid (INH) used as a secondary chemoprophylactic agent was evaluated in 160 adults. Periodic clinical and liver-function evaluations were made during the year of treatment. Sixteen patients (10%) were unable to complete the therapy, 12 of these because of symptomatic reactions. The most frequent symptom complex included fever, myalgias, arthralgias, and nausea or anorexia. Associated elevation of the serum glutamic oxaloacetic transaminase (SGOT) level was frequent, but no patients developed clinical jaundice. The drug was also stopped in four asymptomatic patients because of elevation of the SGOT level to more than 100 units (upper limits of normal 40). The symptomatic reactions and liver-function test abnormalities tended to occur early in therapy. Efforts to detect toxicity should be concentrated in the early weeks of drug administration.
Liver transplantation for Budd–Chiari syndrome: A European study on 248 patients from 51 centres
Authors: Gilles Mentha, Emiliano Giostra, Pietro E. Majno, Wolf O. Bechstein, Peter Neuhaus, John O'Grady, Raaj K. Praseedom, Andrew K. Burroughs, Yves P. Le Treut, Preben Kirkegaard, Xavier Rogiers, Bo-Goran Ericzon, Krister Hockerstedt, René Adam, Juergen Klempnauer
Journal: Journal of Hepatology (2005)