tbuckley/cabot-search huggingface dataset:
Treatment with Monoclonal Antibodies against<i>Clostridium difficile</i>Toxins
Authors: Israel Lowy, Deborah C. Molrine, Brett A. Leav, Barbra M. Blair, Roger Baxter, Dale N. Gerding, Geoffrey Nichol, William D. Thomas, Mark Leney, Susan Sloan, Catherine A. Hay, Donna M. Ambrosino
Journal: New England Journal of Medicine (2010)

New therapies are needed to manage the increasing incidence, severity, and high rate of recurrence of Clostridium difficile infection.We performed a randomized, double-blind, placebo-controlled study of two neutralizing, fully human monoclonal antibodies against C. difficile toxins A (CDA1) and B (CDB1). The antibodies were administered together as a single infusion, each at a dose of 10 mg per kilogram of body weight, in patients with symptomatic C. difficile infection who were receiving either metronidazole or vancomycin. The primary outcome was laboratory-documented recurrence of infection during the 84 days after the administration of monoclonal antibodies or placebo.Among the 200 patients who were enrolled (101 in the antibody group and 99 in the placebo group), the rate of recurrence of C. difficile infection was lower among patients treated with monoclonal antibodies (7% vs. 25%; 95% confidence interval, 7 to 29; P<0.001). The recurrence rates among patients with the epidemic BI/NAP1/027 strain were 8% for the antibody group and 32% for the placebo group (P=0.06); among patients with more than one previous episode of C. difficile infection, recurrence rates were 7% and 38%, respectively (P=0.006). The mean duration of the initial hospitalization for inpatients did not differ significantly between the antibody and placebo groups (9.5 and 9.4 days, respectively). At least one serious adverse event was reported by 18 patients in the antibody group and by 28 patients in the placebo group (P=0.09).The addition of monoclonal antibodies against C. difficile toxins to antibiotic agents significantly reduced the recurrence of C. difficile infection. (ClinicalTrials.gov number, NCT00350298.)
Identification of Optimal Drug Combinations Targeting Cellular Networks: Integrating Phospho-Proteomics and Computational Network Analysis
Authors: Sergio Iadevaia, Yiling Lu, Fabiana C. Morales, Gordon B. Mills, Prahlad T. Ram
Journal: Cancer Research (2010)

Targeted therapeutics hold tremendous promise in inhibiting cancer cell proliferation. However, targeting proteins individually can be compensated for by bypass mechanisms and activation of regulatory loops. Designing optimal therapeutic combinations must therefore take into consideration the complex dynamic networks in the cell. In this study, we analyzed the insulin-like growth factor (IGF-1) signaling network in the MDA-MB231 breast cancer cell line. We used reverse-phase protein array to measure the transient changes in the phosphorylation of proteins after IGF-1 stimulation. We developed a computational procedure that integrated mass action modeling with particle swarm optimization to train the model against the experimental data and infer the unknown model parameters. The trained model was used to predict how targeting individual signaling proteins altered the rest of the network and identify drug combinations that minimally increased phosphorylation of other proteins elsewhere in the network. Experimental testing of the modeling predictions showed that optimal drug combinations inhibited cell signaling and proliferation, whereas nonoptimal combination of inhibitors increased phosphorylation of nontargeted proteins and rescued cells from cell death. The integrative approach described here is useful for generating experimental intervention strategies that could optimize drug combinations and discover novel pharmacologic targets for cancer therapy.
Tumor-Associated Macrophages Promote Angiogenesis and Melanoma Growth via Adrenomedullin in a Paracrine and Autocrine Manner
Authors: Peiwen Chen, Yujie Huang, Rosabel Bong, Yanping Ding, Nan Song, Xiaofeng Wang, Xiaomin Song, Yongzhang Luo
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Elevated numbers of tumor-associated macrophages (TAM) in the tumor microenvironment are often correlated with poor prognosis in melanoma. However, the mechanisms by which TAMs modulate melanoma growth are still poorly understood. This study was aimed at examining the function and mechanism of TAM-derived adrenomedullin (ADM) in angiogenesis and melanoma growth. Experimental Design: We established in vitro and in vivo models to investigate the relationship between TAMs and ADM in melanoma, the role and mechanism of ADM in TAM-induced angiogenesis and melanoma growth. The clinical significance of ADM and its receptors was evaluated using melanoma tissue microarrays. Results: ADM was expressed by infiltrating TAMs in human melanoma, and its secretion from macrophages was upregulated upon coculture with melanoma cells, or with melanoma cells conditioned media. Meanwhile, TAMs enhanced endothelial cell migration and tubule formation and also increased B16/F10 tumor growth. Neutralizing ADM antibody and ADM receptor antagonist, AMA, attenuated TAM-induced angiogenesis in vitro and melanoma growth in vivo, respectively. Furthermore, ADM promoted angiogenesis and melanoma growth via both the paracrine effect, mediated by the endothelial nitric oxide synthase signaling pathway, and the autocrine effect, which stimulated the polarization of macrophages toward an alternatively activated (M2) phenotype. Finally, immunofluorescence analysis on human melanomas showed that the expression of ADM in TAMs and its receptors was greatly increased compared with adjacent normal skins. Conclusion: Our study reveals a novel mechanism that TAMs enhance angiogenesis and melanoma growth via ADM and provides potential targets for melanoma therapies. Clin Cancer Res; 17(23); 7230–9. ©2011 AACR.
Influenza pneumonia: a comparison between seasonal influenza virus and the H1N1 pandemic
Authors: R. Riquelme, A. Torres, M.L. Rioseco, S. Ewig, C. Cillóniz, M. Riquelme, C. Inzunza, E. Polverino, Y. Gomez, M.A. Marcos, C. Contreras, A. Gabarrús, R. Fasce
Journal: European Respiratory Journal (2010)

We compared clinical presentation, complications and outcome in patients with influenza A (H1N1) and seasonal influenza pneumonia. The group of patients with influenza A (H1N1) pneumonia consisted of 75 patients. 52 patients with pneumonia associated with seasonal influenza were included for comparison. Patients with pneumonia associated with novel H1N1 influenza were younger (mean age 39.7 yrs versus 69.6 yrs) and had fewer chronic comorbidities and less alcoholism. Infiltrates were more extensive and frequently interstitial. Respiratory failure was more frequent (those with an arterial oxygen tension/inspiratory oxygen fraction ratio &lt;200 28% versus 12%, p = 0.042), leading to a higher rate of intensive care unit (ICU) admission and mechanical ventilation (29.3% versus 7.7% (p&lt;0.0030) and 18.7% versus 2% (p&lt;0.0045)). Mortality was twice as high in patients with novel H1N1 (12% versus 5.8%; p = 0.238), although this was not significant, and was attributable to pneumonia in most instances (77.8% versus 0%; p = 0.046). Younger age, fewer comorbidities, more extensive radiographic extension and more severe respiratory compromise, and ICU admissions are key features of the clinical presentation of patients with novel H1N1-associated pneumonia compared with seasonal influenza pneumonia.
Frostbite: incidence and predisposing factors in mountaineers
Authors: I Harirchi, A Arvin, J H Vash, V Zafarmand
Journal: British Journal of Sports Medicine (2005)

Frostbite, the most common cold injury, occurs in mountaineers, a major group at risk, more often than in the general population.To describe the incidence of frostbite and the situations associated with it in mountaineering, emphasising factors that can be modified to decrease its frequency and severity.In this cross sectional, questionnaire based study, 637 mountaineers were asked if they had suffered any frostbite injuries during the preceding two years and to provide the personal and circumstantial details.The mean incidence was 366/1000 population per year. Grade 1 injury (83.0%) and hands (26.4%) and feet (24.1%) involvement were most common. There was a significant relation between lack of proper equipment (odds ratio 14.3) or guide (p<0.001) and the injury. Inappropriate clothing, lack or incorrect use of equipment, and lack of knowledge of how to deal with cold and severe weather were claimed to be the main reasons for the injury.In high altitude and winter expeditions, mountaineers should wear appropriate clothing, have the necessary equipment such as quality boots and mittens, use a competent guide, and have training on how to tackle cold weather. They should also avoid wet clothing, windy terrains, and should never remain in the same position for long periods to reduce the risk of cold injuries.
Rapidly progressive sacroiliitis in a patient with lymphocytic lymphoma.
Authors: M R Cohen, G E Carrera, J Lundberg
Journal: Annals of the Rheumatic Diseases (1993)

Rheumatological manifestations may develop as paraneoplastic syndromes in patients with malignancy. Sacroiliitis and spondyloarthropathy have not, however, been previously associated with cancer. The case is described of a patient with a stage IV diffuse well differentiated lymphocytic lymphoma who developed concomitant sacroiliitis and enthesopathies with rapid progression following the diagnosis of malignancy.
Neoplasms in Strains of Splenectomized Mice After a Single 7, 12-Dimethylbenz [a]anthracene Treatmentl 2
Authors: Yasuyuki Akamatsus
Journal: JNCI Journal of the National Cancer Institute (1975)

Journal Article Neoplasms in Strains of Splenectomized Mice After a Single 7, 12-Dimethylbenz [a]anthracene Treatmentl Get access Yasuyuki Akamatsus Yasuyuki Akamatsus Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 55, Issue 4, October 1975, Pages 893–897, https://doi.org/10.1093/jnci/55.4.893 Published: 01 October 1975 Article history Received: 29 January 1975 Accepted: 03 June 1975 Published: 01 October 1975
Neurotransmitter Control of Sinoatrial Pacemaker Frequency in Isolated Rat Atria and in Intact Rabbits
Authors: ALBERT S. GRODNER, HANS-GUNTHER LAHRTZ, PETER E. POOL, EUGENE BRAUNWALD
Journal: Circulation Research (1970)

The sinoatrial node is under the control of both parasympathetic and sympathetic influences. To study the interaction between these opposing influences, the response of the frequency of contraction of a spontaneously contracting rat right atrium to combinations of the neurotransmitters, norepinephrine and acetylcholine was observed. Norepinephrine in concentrations of 1 x 10 -7 M, 1 x 10 -6 M, and 1 x 10 -5 M, which by themselves increased atrial frequency by averages of 30%, 51% and 82%, respectively, and acetylcholine in concentrations of 1 x 10 -5 M, 1 x l0 -4 M, and 1 x 10 -3 M, which by themselves decreased atrial frequency by averages of 17%, 52%, and 97%, respectively, were added in all combinations to the atrial preparations. The response was not an algebraic sum of the effects of each of the agents; rather, the bradycrotic influence of acetylcholine predominated in all cases. This action of acetylcholine was blocked by atropine. To evaluate this interaction under more physiologic circumstances, the response of heart rate of anesthetized rabbits to isoproterenol, a potent beta-receptor stimulant, and to asphyxia, a stimulus which produces a marked parasympathetic discharge, was studied. Asphyxia alone induced a marked bradycardia that could be abolished by vagotomy. However, this bradycardia was not prevented by isoproterenol. It is concluded that the predominance of the parasympathetic nervous system on the sinoatrial frequency is a result of the interaction of the neurotransmitters, norepinephrine and acetylcholine on the sinoatrial node. In this interaction the presence of acetylcholine appears to prevent the action of norepinephrine.
Defying birth defects through diet?
Authors: Krista S Crider, Lynn B Bailey
Journal: Genome Medicine (2011)

The risk of certain birth defects can be modified by maternal diet. A high-fat maternal mouse diet has recently been reported to substantially increase the penetrance of birth defects known to be associated with a deficiency of transcription factor Cited2 as well as induce cleft palate. These effects were associated with a more than twofold reduction in embryonic expression of Pitx2c. This investigation suggests the need to further explore this provocative gene-diet interaction in human studies.
Addition of salmeterol to existing treatment in patients with COPD: a 12 month study
Authors: R A Stockley
Journal: Thorax (2006)

<b>Background:</b> This study investigated the addition of salmeterol to existing treatment for exacerbations in patients with poorly reversible chronic obstructive pulmonary disease (COPD). <b>Methods:</b> 634 patients aged &gt;40 years with a history of COPD exacerbations (including at least two in the previous year) and poor reversibility of airflow obstruction (⩽10% predicted forced expiratory volume in 1 second) received either salmeterol 50 μg or placebo twice daily from a Diskus inhaler for 12 months. The primary outcome was the number of moderate and severe exacerbations. <b>Results:</b> The median rate of moderate or severe exacerbations in the intent-to-treat (ITT) population was lower in the salmeterol group (0.00, range 0.0–9.8, n = 316) than in the placebo group (0.93, range 0.0–13.0, n = 318), but the difference was not statistically significant (p = 0.27). The median rate of exacerbations in the per protocol population (&gt;90% compliance) was also found to be lower in the salmeterol group (0.00, range 0.0–5.0, n = 206) than in the placebo group (0.93, range 0.0–5.6, n = 195) and did reach statistical significance (p = 0.007). For secondary end points, patients receiving salmeterol had significant improvement in lung hyperinflation measured by inspiratory capacity which was evident at 4 weeks and maintained over 12 months (p = 0.035), and a significant improvement in health status measured by the St George's Respiratory Questionnaire at 12 months (p = 0.002). <b>Conclusion:</b> Salmeterol has a positive effect on symptoms and health status of patients with COPD when added to usual treatment. Exacerbations are only reduced in patients who comply with treatment.
Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity
Authors: Rachel H. McMahan, Lucy Golden-Mason, Michael I. Nishimura, Brian J. McMahon, Michael Kemper, Todd M. Allen, David R. Gretch, Hugo R. Rosen
Journal: Journal of Clinical Investigation (2010)

Having successfully developed mechanisms to evade immune clearance, hepatitis C virus (HCV) establishes persistent infection in approximately 75%-80% of patients. In these individuals, the function of HCV-specific CD8+ T cells is impaired by ligation of inhibitory receptors, the repertoire of which has expanded considerably in the past few years. We hypothesized that the coexpression of the negative regulatory receptors T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) and programmed death 1 (PD-1) in HCV infection would identify patients at risk of developing viral persistence during and after acute HCV infection. The frequency of PD-1-Tim-3- HCV-specific CTLs greatly outnumbered PD-1+Tim-3+ CTLs in patients with acute resolving infection. Moreover, the population of PD-1+Tim-3+ T cells was enriched for within the central memory T cell subset and within the liver. Blockade of either PD-1 or Tim-3 enhanced in vitro proliferation of HCV-specific CTLs to a similar extent, whereas cytotoxicity against a hepatocyte cell line that expressed cognate HCV epitopes was increased exclusively by Tim-3 blockade. These results indicate that the coexpression of these inhibitory molecules tracks with defective T cell responses and that anatomical differences might account for lack of immune control of persistent pathogens, which suggests their manipulation may represent a rational target for novel immunotherapeutic approaches.
Purinergic axis in cardiac blood vessels. Agonist-mediated release of ATP from cardiac endothelial cells.
Authors: S Yang, D J Cheek, D P Westfall, I L Buxton
Journal: Circulation Research (1994)

Purified endothelial cells isolated from guinea pig hearts by enzymatic perfusion were grown in monolayer culture and used to test the ability of a variety of vasoactive agents to stimulate ATP release from these cells. Stimulation of endothelial cells with the peptide agonist bradykinin (1 nmol/L), acetylcholine (1 mumol/L), serotonin (1 mumol/L), or adenosine 5'-diphosphate (10 mumol/L) resulted in the rapid appearance of ATP in the incubation medium determined with the firefly luciferase assay for ATP. Addition of antagonists for muscarinic (atropine, 0.1 mumol/L) and purinergic (suramin, 100 mumol/L; reactive blue-2, 100 mumol/L) receptors suggested that ATP release from these cells was receptor-mediated. Bradykinin-induced release of ATP was rapid (peak &lt; 30 seconds at 3 nmol/L bradykinin), dose-dependent (EC50, 0.18 nmol/L), and diminished with repeated administration of agonist. Desensitization to bradykinin also affected the ability of acetylcholine to induce release and was reversible when cells were returned to growth conditions for short periods. Measurement of released adenyl purines as their fluorescent N6-ethenopurine derivatives by high-performance liquid chromatography revealed the origin of the purine released to be ATP and confirmed its rapid dephosphorylation. Addition of the purine nucleotide analogues 2-methylthio-ATP (2-methyl-S-ATP), ADP, and beta gamma-methylene ATP to endothelial cell cultures resulted in a dose-dependent increase in the appearance of ATP measured in the medium bathing the cells at 30 seconds, suggesting the presence of ATP-induced ATP release.(ABSTRACT TRUNCATED AT 250 WORDS)
CILOSTAZOL, A PHOSPHODIESTERASE III INHIBITOR, INCREASES CAMP LEVELS AND AUGMENTS THE INFARCT SIZE LIMITING EFFECT OF A DPP4 INHIBITOR IN MICE WITH TYPE-2 DIABETES MELLITUS
Authors: Yochai Birnbaum, Shukuan Ling, Alexander Castillo, Jose R. Perez-Polo, Yumei Ye
Journal: Journal of the American College of Cardiology (2012)
PSYCHIATRIC TREATMENT OF THE VETERAN OUTPATIENT
Authors: JOSEPH HUGHES, BLAINE E. MCLAUGHLIN
Journal: American Journal of Psychiatry (1948)

1. With skilled and positively directed psychotherapy and a well-integrated clinic setup, the veteran patient suffering from service-connected psychoneurotic disorder may be expected to be supporting himself and working each day after a period of 12 weeks of treatment (12 interviews). 2. The patient whose neurotic symptoms are an expression of emotional instability based on life-long faulty habit patterns may also be expected to respond favorably if well motivated. Thirty-two of 47 such patients in this group are working and have gained healthful insight into the emotional nature of their symptoms through psychotherapy. 3. Schizophrenic patients may be carried along on an outpatient basis providing they have partial insight and are not too unpredictably aggressive. 4. From the standpoint of recovery it can be said that adequate outpatient care is the first step to be taken in any treatment effort directed to restore the veteran patient to healthy relationships with his family and the community.
Interactions between integrin αIIbβ3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans
Authors: Ana Marin D. Carneiro, Edwin H. Cook, Dennis L. Murphy, Randy D. Blakely
Journal: Journal of Clinical Investigation (2008)

The essential contribution of the antidepressant-sensitive serotonin (5-HT) transporter SERT (which is encoded by the SLC6A4 gene) to platelet 5-HT stores suggests an important role of this transporter in platelet function. Here, using SERT-deficient mice, we have established a role for constitutive SERT expression in efficient ADP- and thrombin-triggered platelet aggregation. Additionally, using pharmacological blockers of SERT and the vesicular monoamine transporter (VMAT), we have identified a role for ongoing 5-HT release and SERT activity in efficient human platelet aggregation. We have also demonstrated that fibrinogen, an activator of integrin αIIbβ3, enhances SERT activity in human platelets and that integrin αIIbβ3 interacts directly with the C terminus of SERT. Consistent with these findings, knockout mice lacking integrin β3 displayed diminished platelet SERT activity. Conversely, HEK293 cells engineered to express human SERT and an activated form of integrin β3 exhibited enhanced SERT function that coincided with elevated SERT surface expression. Our results support an unsuspected role of αIIbβ3/SERT associations as well as αIIbβ3 activation in control of SERT activity in vivo that may have broad implications for hyperserotonemia, cardiovascular disorders, and autism.
Identification and validation of gene expression models that predict clinical outcome in patients with early-stage laryngeal cancer
Authors: E. Fountzilas, K. Markou, K. Vlachtsis, A. Nikolaou, P. Arapantoni-Dadioti, E. Ntoula, G. Tassopoulos, M. Bobos, P. Konstantinopoulos, G. Fountzilas, D. Spentzos
Journal: Annals of Oncology (2012)
Impact of methicillin resistance on mortality in Staphylococcus aureus VAP: a systematic review
Authors: Z. Athanassa, I. I. Siempos, M. E. Falagas
Journal: European Respiratory Journal (2008)

The aim of the present study was to estimate the impact of methicillin resistance on mortality in ventilator-associated pneumonia (VAP) due to Staphylococcus aureus . PubMed, Scopus and the bibliographies of the eligible studies were searched. The DerSimonian-Laird random effects model was used to determine the effect of methicillin resistance on mortality. Eight articles were included. Crude in-hospital mortality was higher in patients with VAP due to methicillin-resistant S. aureus (MRSA) than in those with VAP due to methicillin-sensitive S. aureus (MSSA). This was also the case for crude intensive care unit mortality. However, three of the selected studies, which adjusted for potential confounding factors, including adequacy of empirical treatment and severity of illness, demonstrated no difference in in-hospital mortality between patients with MRSA and MSSA VAP. This was not the case for another eligible study that also made adjustment, but for confounders other than those shown above. The limited available evidence seems to suggest that methicillin resistance is associated with death among persons acquiring Staphylococcus aureus ventilator-associated pneumonia. However, although supported by even more limited data, adjustment for risk factors suggests that this association may not be causal, but probably due to confounders, such as the adequacy of empirical treatment and severity of illness.