tbuckley/cabot-search huggingface dataset:
F14512, a Potent Antitumor Agent Targeting Topoisomerase II Vectored into Cancer Cells via the Polyamine Transport System
Authors: Jean-Marc Barret, Anna Kruczynski, Stéphane Vispé, Jean-Philippe Annereau, Viviane Brel, Yves Guminski, Jean-Guy Delcros, Amélie Lansiaux, Nicolas Guilbaud, Thierry Imbert, Christian Bailly
Journal: Cancer Research (2008)

The polyamine transport system (PTS) is an energy-dependent machinery frequently overactivated in cancer cells with a high demand for polyamines. We have exploited the PTS to selectively deliver a polyamine-containing drug to cancer cells. F14512 combines an epipodophyllotoxin core-targeting topoisomerase II with a spermine moiety introduced as a cell delivery vector. The polyamine tail supports three complementary functions: (a) facilitate formulation of a water-soluble compound, (b) increase DNA binding to reinforce topoisomerase II inhibition, and (c) facilitate selective uptake by tumor cells via the PTS. F14512 is 73-fold more cytotoxic to Chinese hamster ovary cells compared with CHO-MG cells with a reduced PTS activity. A decreased sensitivity of L1210 leukemia cells to F14512 was observed in the presence of putrescine, spermidine, and spermine. In parallel, the spermine moiety considerably enhances the drug-DNA interaction, leading to a reinforced inhibition of topoisomerase II. The spermine tail of F14512 serves as a cell delivery vehicle as well as a DNA anchor, and this property translates at the cellular level into a distinct pharmacologic profile. Twenty-nine human solid or hematologic cell lines were used to characterize the high cytotoxic potential of F14512 (median IC50 of 0.18 micromol/L). Finally, the potent antitumor activity of F14512 in vivo was evidenced with a MX1 human breast tumor xenograft model, with partial and complete tumor regressions. This work supports the clinical development of F14512 as a novel targeted cytotoxic drug and sheds light on the concept of selective delivery of drugs to tumor cells expressing the PTS.
THE RELATIONSHIP BETWEEN THE ACUTE PHASE RESPONSE AND ANTIBODY PRODUCTION IN THE RABBIT
Authors: Harrison F. Wood
Journal: The Journal of Experimental Medicine (1953)

It has been found that some rabbits respond to the administration of either human C-reactive protein or human gamma globulin with the production of an acute phase substance, Cx-reactive protein. A correlation was found to exist between the amount of Cx-protein produced and the subsequent production of significant titers of precipitating antibody to the two antigens employed.
Observations on the "Lausanne Recommendations" on sudden cardiovascular death in sport
Authors: Bruce Hamilton, Rod Jaques, Richard Budgett
Journal: British Journal of Sports Medicine (2007)

Observations on the ''Lausanne Recommendations'' on sudden cardiovascular death in sportAs Directors of Medical Services to UK Athletics, the English Institute of Sport and the British Olympic Association, we were pleased to receive the Lausanne Recommendations on Preparticipation Cardiovascular Screening for Sudden Cardiovascular Death in Sport. 1 We fully support the goals and motivations behind this document, but having carefully read the document, there are a number of areas that may warrant open discussion.The following dissertation outlines those areas of the recommendations that we, as practising sports physicians charged with their implementation, believe require further delineation and clarity.Our hope is that further discussion will result in enhanced clarity and help on the implementation of these recommendations.
Sequential Versus Simultaneous Biventricular Resynchronization for Severe Heart Failure
Authors: Peter Sogaard, Henrik Egeblad, Anders K. Pedersen, Won Yong Kim, Bent Ø. Kristensen, Peter S. Hansen, Peter T. Mortensen
Journal: Circulation (2002)

Cardiac resynchronization therapy (CRT) by means of simultaneous biventricular pacing improves left ventricular systolic performance and synchrony in patients with heart failure and bundle-branch block. We used tissue tracking and 3D echocardiography to evaluate the impact of sequential CRT with individualized interventricular delay programming.Twenty consecutive patients with severe heart failure and left bundle-branch block were included. Tissue tracking and 3D echocardiography were carried out before and on the day after pacemaker implantation. Eleven different interventricular delays were examined in each patient. Patients were reexamined after 3 months. Simultaneous CRT immediately reduced the extent of myocardium displaying delayed longitudinal contraction (DLC) from 48.6+/-16% to 23.2+/-13% (P<0.01) and increased left ventricular ejection fraction percentage (LVEF%) from 22.4+/-6% to 29.7+/-5% (P<0.01). However, optimum sequential CRT caused a further reduction in the extent of DLC from 23.2+/-13% to 11.1+/-7.2% (P<0.01), with a simultaneous increase in LVEF% (from 29.7+/-5% to 33.9+/-6%, P<0.01). Three months of optimum sequential CRT further improved LVEF% (from 33.6+/-6% to 38.6+/-7.2%, P<0.01). Tissue tracking detected the segments with DLC, and their location determined optimum interventricular delay programming. Compared with simultaneous CRT, sequential CRT increased diastolic filling time by 7+/-2.5%.Compared with simultaneous CRT, sequential CRT significantly improves left ventricular systolic and diastolic performance. Tissue tracking can be used to select optimum interventricular delay during CRT.
Advances in the treatment of gastrointestinal stromal tumours
Authors: I. Judson, G. Demetri
Journal: Annals of Oncology (2007)

Imatinib, a selective tyrosine kinase inhibitor, is currently the standard of care first-line treatment for unresectable or metastatic gastrointestinal stromal tumour (GIST), improving survival time and delaying disease progression in many patients. Nevertheless, primary and secondary (acquired) resistance to imatinib is a substantial problem in routine clinical practice. Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that was approved for the treatment of imatinib-resistant or -intolerant GIST. In the pivotal phase III study, sunitinib provided substantial clinical benefits including disease control and superior survival versus placebo as second-line treatment. Treatment with sunitinib was reasonably well tolerated. The availability of sunitinib represents an important clinical advance in GIST management, providing physicians and patients with an effective therapy when resistance to imatinib develops.
An obligate cell-intrinsic function for CD28 in Tregs
Authors: Ruan Zhang, Alexandria Huynh, Gregory Whitcher, JiHoon Chang, Jonathan S. Maltzman, Laurence A. Turka
Journal: Journal of Clinical Investigation (2013)

Tregs expressing the transcription factor FOXP3 are critical for immune homeostasis. The costimulatory molecule CD28 is required for optimal activation and function of naive T cells; however, its role in Treg function has been difficult to dissect, as CD28 is required for thymic Treg development, and blockade of CD28-ligand interactions has confounding effects in trans on nonregulatory cells. To address this question, we created Treg-specific Cd28 conditional knockout mice. Despite the presence of normal numbers of FOXP3+ cells, these animals accumulated large numbers of activated T cells, developed severe autoimmunity that primarily affected the skin and lungs, and failed to appropriately resolve induced experimental allergic encephalomyelitis. This in vivo functional impairment was accompanied by dampened expression of CTLA-4, PD-1, and CCR6. Disease occurrence was not due to subversion of Cd28-deficient Tregs into pathogenic cells, as complementation with normal Tregs prevented disease occurrence. Interestingly, in these "competitive" environments, Cd28-deficient Tregs exhibited a pronounced proliferative/survival disadvantage. These data demonstrate clear postmaturational roles for CD28 in FOXP3+ Tregs and provide mechanisms which we believe to be novel to explain how interruption of CD28-ligand interactions may enhance immune responses independent of effects on thymic development or on other cell types.
S<scp>IGNALING AT THE</scp> G<scp>ROWTH</scp> C<scp>ONE</scp>: Ligand-Receptor Complexes and the Control of Axon Growth and Guidance
Authors: Andrea B. Huber, Alex L. Kolodkin, David D. Ginty, Jean-François Cloutier
Journal: Annual Review of Neuroscience (2003)

▪ Abstract The guidance of axons during the establishment of the nervous system is mediated by a variety of extracellular cues that govern cytoskeletal dynamics in axonal growth cones. A large number of these guidance cues and their cell-surface receptors have now been identified, and the intracellular signaling pathways by which these cues induce cytoskeletal rearrangements are becoming defined. This review summarizes our current understanding of the major families of axon guidance cues and their receptors, with a particular emphasis on receptor signaling mechanisms. We also discuss recent advances in understanding receptor cross talk and how the activities of guidance cues and their receptors are modulated during neural development.
Functional characterization of a stable, noncytolytic stage of macrophage activation in tumors.
Authors: S W Russell, W F Doe, A T McIntosh
Journal: The Journal of Experimental Medicine (1977)

The state in which macrophages (Mphi) from regressing Moloney sarcomas could kill tumor target cells was a highly labile one which decayed rapidly in vitro. Thereafter, regressor Mphi were noncytolytic. Mphi from several different progressing sarcomas failed to kill, even when challenged with target cells immediately after explantation. Similarly, thioglycollate-induced peritoneal Mphi (TG-Mphi) did not kill. Noncytolygic Mphi derived either from progressing sarcomas or from long-term (up to 96 h) cultures of regressor Mphi were exquisitely sensitive to stimulation by bacterial lipopolysaccharide (LPS); picogram/milliliter amounts induced killing. Similar concentrations of LPS had no demonstrable effect on TG-Mphi. Thus, tumor Mphi generally appeared to have been primed in vivo, with those in regressing sarcomas having additionally acquired cytolytic activity. Inability of progressor Mphi to kill apparently stemmed from lack of, or failure to respond to, the signal needed in vivo to trigger cytolytic activity, rather than the total absence of activation.
Differential pathways for the interleukin-1β production activated by chromogranin A and Aβ in microglia
Authors: Zhou Wu, Hiroshi Nakanishi
Journal: Molecular Neurodegeneration (2013)

Materials and methods MG6 microglia and primary cultured microglia were used in this study. Microglia isolated from young and aged mouse brains by magnetic cell sorting using CD11b-conjugated microbeads were also used. Processings of pro-caspase-1 and pro-IL-1b were analysed by immunoblottings. Secretion of IL-1b was measured by ELISA. The frontal cortex of human brains from AD and no clinical evidence of dementia were used for immunohistochemical analyses.
Correlation of Individual Differences in Schizotypal Personality Traits With Amphetamine-Induced Dopamine Release in Striatal and Extrastriatal Brain Regions
Authors: Neil D. Woodward, Ronald L. Cowan, Sohee Park, M. Sib Ansari, Ronald M. Baldwin, Rui Li, Mikisha Doop, Robert M. Kessler, David H. Zald
Journal: American Journal of Psychiatry (2010)

Objective: Schizotypal personality traits are associated with schizophrenia spectrum disorders, and individuals with schizophrenia spectrum disorders demonstrate increased dopamine transmission in the striatum. The authors sought to determine whether individual differences in normal variation in schizotypal traits are correlated with dopamine transmission in the striatum and in extrastriatal brain regions. Method: Sixty-three healthy volunteers with no history of psychiatric illness completed the Schizotypal Personality Questionnaire and underwent positron emission tomography imaging with [18F]fallypride at baseline and after administration of oral d-amphetamine (0.43 mg/kg). Dopamine release, quantified by subtracting each participant's d-amphetamine scan from his or her baseline scan, was correlated with Schizotypal Personality Questionnaire total and factor scores using region-of-interest and voxel-wise analyses. Results: Dopamine release in the striatum was positively correlated with overall schizotypal traits. The association was especially robust in the associative subdivision of the striatum. Voxel-wise analyses identified additional correlations between dopamine release and schizotypal traits in the left middle frontal gyrus and left supramarginal gyrus. Exploratory analyses of Schizotypal Personality Questionnaire factor scores revealed correlations between dopamine release and disorganized schizotypal traits in the striatum, thalamus, medial prefrontal cortex, temporal lobe, insula, and inferior frontal cortex. Conclusions: The association between dopamine signaling and psychosis phenotypes extends to individual differences in normal variation in schizotypal traits and involves dopamine transmission in both striatal and extrastriatal brain regions. Amphetamine-induced dopamine release may be a useful endophenotype for investigating the genetic basis of schizophrenia spectrum disorders.
Chorea in systemic lupus erythematosus: association with antiphospholipid antibodies.
Authors: M A Khamashta, A Gil, B Anciones, P Lavilla, M E Valencia, V Pintado, J J Vazquez
Journal: Annals of the Rheumatic Diseases (1988)

Chorea is a rare manifestation of systemic lupus erythematosus (SLE). In this report the clinical features of two cases of chorea associated with SLE are presented. Of special interest were the raised titres of antiphospholipid antibodies in both cases. The possible pathogenic role of these antibodies is briefly discussed.
Phase III Study of Cyclophosphamide, Doxorubicin, and Fluorouracil (CAF) Plus Leucovorin Versus CAF for Metastatic Breast Cancer: Cancer and Leukemia Group B 9140
Authors: H.L. Parnes, C. Cirrincione, J. Aisner, D.A. Berry, S.L. Allen, J. Abrams, E. Chuang, M.R. Cooper, M.C. Perry, D.B. Duggan, T.P. Szatrowski, I.C. Henderson, L. Norton
Journal: Journal of Clinical Oncology (2003)

To determine whether biochemical modulation with LV (leucovorin) enhances the efficacy of CAF (cyclophosphamide, doxorubicin, and fluorouracil) against metastatic breast cancer.Women with histologically confirmed stage IV breast cancer, Cancer and Leukemia Group B (CALGB) performance status 0 to 2, and no prior chemotherapy for metastatic disease were randomly assigned to receive CAF (cyclophosphamide 500 mg/m2 day 1, doxorubicin 40 mg/m2 day 1, and fluorouracil [FU] 200 mg/m2 intravenous bolus days 1 to 5) with or without LV (LV 200 mg/m2 over 30 minutes days 1 to 5 given 1 hour before FU).Two hundred forty-two patients were randomly assigned to treatment; 124 patients had visceral crisis and 40 patients had a CALGB performance status score of 2. The median follow-up was 6 years. The two study arms were similar with regard to serious adverse events; four patients died from treatment-related causes, two patients on each study arm. Predictive variables for time to treatment failure and survival were visceral disease and performance status. The overall response rate was 29% for CAF versus 28% for CAF plus LV. The median time to treatment failure (9 months) and median survival (1.7 years) did not differ by treatment arm.Modulation of CAF with LV improved neither response rates nor survival among women with metastatic breast cancer, compared with CAF alone. Multivariate analyses confirmed the prognostic importance of performance status and visceral crisis. However, the overall and complete response rates, response durations, time to treatment failure, and survival were the same in the two treatment arms.
Effects of Increased Residual Volume, Increased Output Resistance and Autonomic Drugs on Ventricular Suction in the Turtle
Authors: JAMES C. KRANER
Journal: Circulation Research (1959)

Immersed, isolated turtle ventricles were allowed to beat when filling only by suction. Obstruction of ejection at various volumes showed an inverse relationship between residual volume and volume aspirated. Diastolic aspiration occurred even with residual volumes of at least 0.55 ml. Ventricles, filling by suction only, maintained continuous output of up to 3 ml./min. working against pressures of 16 to 22 cm. H 2 O. In these circumstances ejection was diminished or abolished by acetylcholine and usually increased by epinephrine. This work amplifies and further quantitates recent work showing ventricular diastolic suction in a variety of species.
Gene Expression in Fibroblasts and Fibrosis
Authors: Ichiro Manabe, Takayuki Shindo, Ryozo Nagai
Journal: Circulation Research (2002)

Structural remodeling of the ventricular wall is a key determinant of clinical outcome in heart disease. Such remodeling involves the production and destruction of extracellular matrix proteins, cell proliferation and migration, and apoptotic and necrotic cell death. Cardiac fibroblasts are crucially involved in these processes, producing growth factors and cytokines that act as autocrine and paracrine factors, as well as extracellular matrix proteins and proteinases. Recent studies have shown that the interactions between cardiac fibroblasts and cardiomyocytes are essential for the progression of cardiac remodeling. This review addresses the functional role played by cardiac fibroblasts and the molecular mechanisms that govern their activity during cardiac hypertrophy and remodeling. A particular focus is the recent progress toward our understanding of the transcriptional regulatory mechanisms involved.
Tobacco Smoke Exposure Is Associated With the Metabolic Syndrome in Adolescents
Authors: Michael Weitzman, Stephen Cook, Peggy Auinger, Todd A. Florin, Stephen Daniels, Michael Nguyen, Jonathan P. Winickoff
Journal: Circulation (2005)

Background— The metabolic syndrome predicts future coronary artery disease and type II diabetes and often emerges in childhood. Tobacco smoke potentially contributes to insulin resistance in this syndrome. This study evaluates the association of environmental tobacco smoke (ETS) exposure and active smoking with the prevalence of the metabolic syndrome in US adolescents. Methods and Results— Data from 2273 subjects 12 to 19 years of age were examined from the National Health and Nutrition Examination Survey III (NHANES III, 1988 to 1994). Serum cotinine levels, presence of household smokers, and self-report of smoking were used to determine ETS exposure and active smoking. The metabolic syndrome was defined as having ≥3 criteria from the National Cholesterol Education Panel definition. Bivariate and multivariable analyses were conducted. Among adolescents, 5.6% met the criteria for metabolic syndrome, and prevalence increased with tobacco exposure: 1.2% for nonexposed, 5.4% for those exposed to ETS, and 8.7% for active smokers ( P &lt;0.001). In adolescents at risk for overweight and overweight adolescents (body mass index above the 85th percentile), a similar relationship was observed: 5.6% for nonexposed, 19.6% for those exposed to ETS, and 23.6% for active smokers ( P =0.01). In multivariable logistic regression analyses among all adolescents, ETS exposure was independently associated with the metabolic syndrome (ETS exposure: odds ratio, 4.7, 95% CI, 1.7 to 12.9; active smoking: odds ratio, 6.1; 95% CI, 2.8 to 13.4). Conclusions— Considering that tobacco and obesity are the 2 leading causes of preventable death in the United States, these findings of a dose-response, cotinine-confirmed relationship between tobacco smoke and metabolic syndrome among adolescents may have profound implications for the future health of the public.
Serotonin Reuptake Inhibitor (Paxil) Does Not Prevent the Vasovagal Reaction Associated With Carotid Sinus Massage and/or Lower Body Negative Pressure in Healthy Volunteers
Authors: Theodore S. Takata, Stephen L. Wasmund, Michael L. Smith, Jian-Ming Li, Jose A. Joglar, Kim Banks, Robert C. Kowal, Richard L. Page, Mohamed H. Hamdan
Journal: Circulation (2002)

The purpose of this study was to assess the effect of the serotonin reuptake inhibitor paroxetine hydrochloride (Paxil, SmithKline Beecham) on cardiovascular reflexes. We hypothesized that Paxil prevents neurally mediated syncope (NMS) by attenuating the sympathoinhibition and vagotonia associated with a vasovagal reaction.In a double-blind randomized study, 25 healthy subjects with a positive response to either carotid sinus massage (CSM) or lower body negative pressure (LBNP) received Paxil (20 mg/d) or placebo for 6 weeks. Arterial baroreflex sensitivity (BRS), muscle sympathetic nerve activity (SNA), baroreflex control of SNA, blood pressure, and heart rate responses to CSM and LBNP were measured at baseline and at 6 weeks. Nineteen subjects completed the study (Paxil, n=9; placebo, n=10). In the Paxil group, BRS decreased significantly compared with baseline (15.8+/-4.0 ms/mm Hg versus 11.0+/-2.6 ms/mm Hg, P=0.05); however, all 9 subjects continued to have a positive response to LBNP with presyncope. Paxil did not attenuate the sympathoinhibition or vagotonia associated with a positive LBNP response and had no significant effect on baroreflex control of SNA. In the control group, no significant change in BRS was noted compared with baseline. Seven out of 9 subjects who had a positive LBNP response at baseline had a repeat positive LBNP response, and the subject with a positive CSM at baseline had a negative response at 6 weeks.Paxil decreases arterial BRS but does not prevent the presyncope associated with LBNP. The effect of Paxil on the autonomic reflexes in patients with neurally mediated syncope remains unclear.
Comparison of B‐type natriuretic peptide assays for identifying heart failure in stable elderly patients with a clinical diagnosis of chronic obstructive pulmonary disease
Authors: Frans H. Rutten, Maarten‐Jan M. Cramer, Nicolaas P.A. Zuithoff, Jan‐Willem J. Lammers, Wim Verweij, Diederick E. Grobbee, Arno W. Hoes
Journal: European Journal of Heart Failure (2007)
Inhibition of reactive nitrogen species production in COPD airways: comparison of inhaled corticosteroid and oral theophylline
Authors: T Hirano
Journal: Thorax (2006)

Background: Reactive nitrogen species (RNS) are thought to be one of the important factors in the pathogenesis of chronic obstructive pulmonary disease (COPD).A study was undertaken to examine the effects of theophylline and fluticasone propionate (FP) on RNS production in subjects with COPD.Methods: Sixteen COPD subjects participated in the study.Theophylline (400 mg/day orally) or FP (400 mg/day inhalation) were administered for 4 weeks in a randomised crossover manner with a washout period of 4 weeks.Induced sputum was collected at the beginning and end of each treatment period.3-nitrotyrosine (3-NT), which is a footprint of RNS, was quantified by high performance liquid chromatography with an electrochemical detection method as well as by immunohistochemical staining.Results: Theophylline significantly reduced the level of 3-NT in the sputum supernatant as well as the number of 3-NT positive cells (both p,0.01).FP also reduced 3-NT formation, but the effect was smaller than that of theophylline.Theophylline also significantly reduced the neutrophil cell counts in the sputum (p,0.01), while FP treatment had no effect on the number of inflammatory cells in the sputum, except eosinophils.Conclusions: Theophylline reduces nitrative stress and neutrophil infiltration in COPD airways to a larger extent than inhaled corticosteroid.