tbuckley/cabot-search huggingface dataset:
The Scavenger Receptor MARCO Is Required for Lung Defense against Pneumococcal Pneumonia and Inhaled Particles
Authors: Mohamed Arredouani, Zhiping Yang, YaoYu Ning, Guozhong Qin, Raija Soininen, Karl Tryggvason, Lester Kobzik
Journal: The Journal of Experimental Medicine (2004)

Alveolar macrophages (AMs) express the class A scavenger receptor macrophage receptor with collagenous structure (MARCO), but its role in vivo in lung defense against bacteria and environmental particles has not been studied. We used MARCO-deficient mice to directly test the in vivo role of AM MARCO in innate defense against pneumococcal infection and environmental particles. In a murine model of pneumococcal pneumonia, MARCO−/− mice displayed an impaired ability to clear bacteria from the lungs, increased pulmonary inflammation and cytokine release, and diminished survival. In vitro binding of Streptococcus pneumoniae and in vivo uptake of unopsonized particles by MARCO−/− AMs were dramatically impaired. MARCO−/− mice treated with the “inert” environmental particle TiO2 showed enhanced inflammation and chemokine expression, indicating that MARCO-mediated clearance of inert particles by AMs prevents inflammatory responses otherwise initiated by other lung cells. Our findings point to an important role of MARCO in mounting an efficient and appropriately regulated innate immune response against inhaled particles and airborne pathogens.
Impact of tocilizumab therapy on antibody response to influenza vaccine in patients with rheumatoid arthritis
Authors: Shunsuke Mori, Yukitaka Ueki, Naoyuki Hirakata, Motohiro Oribe, Toshihiko Hidaka, Kazunori Oishi
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> We assessed the influence of tocilizumab (TCZ), a humanised monoclonal anti-interleukin-6 receptor antibody, on antibody response following influenza vaccination in patients with rheumatoid arthritis (RA). <h3>Methods</h3> A total of 194 RA patients received inactive trivalent influenza vaccination (A/H1N1, A/H3N2 and B/B1 strains). All patients were classified into the TCZ (n=62), TCZ+methotrexate (MTX) (n=49), MTX (n=65) and RA control (n=18) groups. Antibody titres were measured before and 4–6 weeks after vaccination using the haemagglutination inhibitory assay. <h3>Results</h3> For the A/H1N1 and A/H3N2 strains, the TCZ and TCZ+MTX groups achieved fold increases of 9.9–14.5, postvaccination seroprotection rates greater than 70% and seroresponse rates greater than 40%. For the B/B1 strain, seroresponse rates were approximately 30%, but fold increases and seroprotection rates were 5.0–5.4 and greater than 70%, respectively, in these treatment groups. MTX had a negative impact on vaccination efficacy, but adequate responses for protection were nevertheless demonstrated in the MTX group. Neither severe adverse effects nor RA flares were observed. <h3>Conclusions</h3> TCZ does not hamper antibody response to influenza vaccine in RA patients. Influenza vaccination is considered effective in protecting RA patients receiving TCZ therapy with or without MTX.
Procalcitonin and C-reactive protein levels in HIV-positive subjects with tuberculosis and pneumonia
Authors: G. K. Schleicher, V. Herbert, A. Brink, S. Martin, R. Maraj, J. S. Galpin, C. Feldman
Journal: European Respiratory Journal (2005)

Pulmonary tuberculosis (PTB) and pneumococcal community-acquired pneumonia (PCAP) are common causes of lower respiratory tract infections in HIV-seropositive patients and may have similar clinical and radiological features. This study aimed to assess the value of serum procalcitonin (PCT) and C-reactive protein (CRP) levels in HIV-seropositive patients with pneumonia, and to investigate their potential role in differentiating pneumococcal from mycobacterial infections. HIV-seropositive patients admitted with pneumonia were evaluated prospectively, 34 with PTB and 33 with PCAP. All 33 patients in the PCAP group and 20 of 34 patients in the PTB group had elevated PCT levels (>0.1 ng x mL(-1)). All patients in both groups had elevated CRP levels (>10 mg x L(-1)). The PTB group had significantly lower CD4 T-lymphocyte counts, lower CRP levels, lower white cell counts, and lower PCT levels than the PCAP group. Receiver operating characteristic analysis showed that optimal discrimination between PTB and PCAP could be performed at a cut-off point of 3 ng x mL(-1) for PCT (sensitivity 81.8%; specificity 82.35%) and 246 mg x L(-1) for CRP (sensitivity 78.8%; specificity 82.3%). In conclusion, HIV-seropositive patients with pneumococcal community-acquired pneumonia had significantly higher procalcitonin and C-reactive protein levels than those with pulmonary tuberculosis. A procalcitonin level >3 ng x mL(-1) and a C-reactive protein level >246 mg x L(-1) were both highly predictive of pneumococcal infection.
Biphasic Adrenergic Modulation of β-Adrenergic Receptors in Man
Authors: Jack F. Tohmeh, Philip E. Cryer
Journal: Journal of Clinical Investigation (1980)

beta-Adrenergic receptors in mononuclear leukocyte preparations were assessed with (-)[(3)H]-dihydroalprenolol binding studies during the infusion of adrenergic agonists into normal human subjects. During the infusion of isoproterenol into seven subjects, mean (+/-SE) (-)[(3)H]dihydroalprenolol binding increased from 25+/-3 fmol/mg protein to 47+/-8 fmol/mg protein (P < 0.02) at 0.5 h and 40+/-3 fmol/mg protein (P < 0.01) at 1 h and decreased to 12+/-1 fmol/mg protein (P < 0.01) at 4-6 h. During the infusion of epinephrine into three subjects, mean (-)[(3)H]dihydroalprenolol binding increased from 32+/-3 to 63+/-3 fmol/mg protein (P < 0.01) at 0.5-1 h. By Scatchard plot analysis, these changes were attributable to changes in the number of available binding sites rather than changes in binding affinity. The observed changes in the number of (-)[(3)H]dihydroalprenolol binding sites were not paralleled by changes in total mononuclear cell counts or in T lymphocyte, B lymphocyte, and monocyte distributions. Thus, we conclude that adrenergic agonists modulate the number of available beta-adrenergic receptors on circulating mononuclear cells in a biphasic manner, with an early increment and a late decrement, in man. Further, the finding that the increase in pulse rate in response to a "pulse" infusion of isoproterenol was significantly greater after 0.5-1 h of agonist infusion suggests that the observed early agonist-induced increment in beta-adrenergic receptor number on circulating cells is paralleled by increments in extra-vascular beta-adrenergic receptor sensitivity.
Inducible Nitric Oxide Synthase Can Be Induced in the Absence of Active Nuclear Factor-κB in Rat Mesangial Cells
Authors: OSAMU NAKASHIMA, YOSHIO TERADA, SEIJI INOSHITA, MICHIO KUWAHARA, SEI SASAKI, FUMIAKI MARUMO
Journal: Journal of the American Society of Nephrology (1999)

Abstract. The contribution of nuclear factor-κB (NF-κB) and interferon-γ (IFN-γ) signaling to nitric oxide generation is not completely understood. The effect of NF-κB release and its inhibition on nitrite production and the involvement of Janus kinase 2 (JAK2) in inducible nitric oxide synthase (iNOS) induction were investigated. The following assays were performed. ( 1 ) Nitrite produced by rat mesangial cells in primary culture was measured in incubations with tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS), with or without IFN-γ. Cells were stimulated with TNF-α or LPS plus IFN-γ in the presence of NF-κB inhibitors, herbimycin A (HerA), or the more specific JAK2 inhibitor AG490. ( 2 ) Immunoblotting was performed against the p65 and p50 subunits of NF-κB and iNOS. ( 3 ) Electrophoretic mobility shift assays were performed against NF-κB in the presence of NF-κB inhibitors or AG490. ( 4 ) iNOS promoter activity was measured in the presence of AG490 or JAK2 antisense oligonucleotides. TNF-α or LPS alone did not induce nitrite production, but with IFN-γ these compounds did induce nitrite production. Pyrrolidine dithiocarbamate (PDTC), N -acetyl-L-cysteine, dexamethasone (Dex), HerA, and AG490 partially inhibited LPS/IFN-γ- or TNF-α/IFN-γ-induced nitrite production. p65 was inhibited by the three NF-κB inhibitors described above, whereas p50 was not. PDTC and Dex completely inhibited the p65/p50 heterodimer, but HerA and AG490 had little effect on p65/p50. AG490 and JAK2 antisense oligonucleotides suppressed iNOS promoter activity. It can be concluded that ( 1 ) iNOS can be induced without active NF-κB; ( 2 ) Dex, acetylsalicylic acid, and PDTC inhibit only p65; and ( 3 ) JAK2 is involved in iNOS induction, and the contribution of JAK2 to nitrite production is greater than that of NF-κB.
CD1d-dependent Activation of NKT Cells Aggravates Atherosclerosis
Authors: Emmanuel Tupin, Antonino Nicoletti, Rima Elhage, Mats Rudling, Hans-Gustaf Ljunggren, Göran K. Hansson, Gabrielle Paulsson Berne
Journal: The Journal of Experimental Medicine (2004)

Adaptive and innate immunity have been implicated in the pathogenesis of atherosclerosis. Given their abundance in the lesion, lipids might be targets of the atherosclerosis-associated immune response. Natural killer T (NKT) cells can recognize lipid antigens presented by CD1 molecules. We have explored the role of CD1d-restricted NKT cells in atherosclerosis by using apolipoprotein E–deficient (apoE−/−) mice, a hypercholesterolemic mouse model that develops atherosclerosis. ApoE−/− mice crossed with CD1d−/− (CD1d−/−apoE−/−) mice exhibited a 25% decrease in lesion size compared with apoE−/− mice. Administration of α-galactosylceramide, a synthetic glycolipid that activates NKT cells via CD1d, induced a 50% increase in lesion size in apoE−/− mice, whereas it did not affect lesion size in apoE−/−CD1d−/− mice. Treatment was accompanied by an early burst of cytokines (IFNγ, MCP-1, TNFα, IL-2, IL-4, IL-5, and IL-6) followed by sustained increases in IFNγ and IL-4 transcripts in the spleen and aorta. Early activation of both T and B cells was followed by recruitment of T and NKT cells to the aorta and activation of inflammatory genes. These results show that activation of CD1d-restricted NKT cells exacerbates atherosclerosis.
Lectures on the Experimental Investigation of the Action of Medicines
Authors: T. L. Brunton
Journal: BMJ (1871)

ARTIFICIAL CIRCULATION OF BLOOD.-A constant supply of arterial blood to all parts of the body is necessary to preserve their vitality ; and if the supply to any part be cut off by stopping its circulation, that part will die.Thus, if the circulation be stopped in an arm or leg by tying its arteries, or through their becoming plugged by emboli, morti- fication, or death of the part, ensues ; and if the heart cease to beat, and the circulation be thus stopped in all parts of the body, they all die.But, if we supply arterial blood artificially to any one part, we may keep it alive at least for a certain time after the rest of the animal is dead; and the muscles may be made to contract, the lungs to excrete carbonic acid, the lymphatics to pour forth lymph, and the excised liver to secrete bile, for hours after the rest of the animal has been consigned to the dust-bin.CIRCULATION OF WARM AND COLD BLOOD.-For this purpose, blood may be used either at the temperature of the room or of the body; but these have not exactly the same effect, and experiments
Infection and hemostasis in decompensated cirrhosis: A prospective study using thrombelastography
Authors: George V. Papatheodoridis, David Patch, George J. Webster, Jim Brooker, Ellie Barnes, Andrew K. Burroughs
Journal: Hepatology (1999)

Bacterial infections are common complications in decompensated cirrhosis, but their relationship with hemostasis has not been studied. We prospectively assessed whether infection affects hemostasis in cirrhosis using routine hemostasis tests and thrombelastography (TEG), a global test of hemostatic function. Eighty-four cirrhotic patients (Child-Pugh B: 26; C: 58) without overt bleeding or blood-product transfusion were prospectively evaluated with routine hemostasis tests and TEG on admission and/or the first day with signs of infection and 5 days later. There were 30 patients with infection; 15 had infection on admission, and 15 developed infection in hospital. In the patients who developed infection in hospital, there was a significant deterioration in all routine hemostasis tests except platelet count (PLT) and in all TEG parameters, on the first day of infection compared with 7 +/- 3 days previously. The same parameters significantly improved from the first day of infection to day 5 and after (P <.02) only in the 22 patients whose infection resolved, while the r, k, and alpha TEG parameters significantly worsened in the 8 patients with persistent infection. In those who developed infection in hospital and were cured (n = 11), the 5-day parameters did not differ from their preinfection values. In conclusion, bacterial infections frequently impair hemostasis in decompensated cirrhotic patients. Successful treatment of infection usually restores hemostasis parameters to preinfection levels in 5 days. Thus, infection may have a role in the bleeding diathesis of cirrhosis.
Simplified Staging for Hepatocellular Carcinoma
Authors: J.-N. Vauthey
Journal: Journal of Clinical Oncology (2002)

PURPOSE: The current American Joint Committee on Cancer (AJCC) staging system for hepatocellular carcinoma (HCC) fails to stratify patients adequately with respect to prognosis. PATIENTS AND METHODS: The ability of the currently proposed tumor (T) categories to effectively stratify the survival of 557 patients who underwent complete resection for HCC at four centers was examined. Independent predictors of survival were combined into a new staging system. RESULTS: Using the current AJCC T classification, patients with T1 and T2 tumors had similar 5-year survivals (P = .6). In addition, the survival of patients with multiple bilobar tumors (T4) matched that of T3 patients (P = .5). Independent predictors of death were major vascular invasion (P < .001), microvascular invasion (P = .001), severe fibrosis/cirrhosis of the host liver (P = .001), multiple tumors (P = .007), and tumor size greater than 5 cm (P = .01). Based on our results, a simplified stratification is proposed: (a) patients with a single tumor and no microvascular invasion, (b) patients with a single tumor and microvascular invasion or multiple tumors, none more than 5 cm, and (c) patients with either multiple tumors, any more than 5 cm, or tumor with major vascular invasion (P < .001). Severe fibrosis/cirrhosis had a negative impact on survival within all categories. The survival of patients with lymph node involvement matched that of patients with major vascular invasion (P = .3). CONCLUSION: The current AJCC staging system for HCC is unnecessarily complex. We propose a simplified model of stratification that is based on vascular invasion, tumor number, and tumor size and incorporates the effect of fibrosis on survival.
The reversible effect of lignocaine on the stimulated metabolic activity of bronchoalveolar lavage cells
Authors: M Duddridge, CA Kelly, C Ward, DJ Hendrick, EH Walters
Journal: European Respiratory Journal (1990)

Lignocaine concentrations were measured in the aspirate from a low volume (100 ml) bronchoalveolar lavage (BAL) in twenty patients who had received topical 4% lignocaine as required, and compared to those found in the aspirate from a 180 ml BAL in ten patients who had received 1.5% isotonic lignocaine. The median BAL supernatant lignocaine concentration was significantly lower at 0.14 mM (range 0.07-0.44 mM) in the group who received 1.5% lignocaine, compared to 1.08 mM (range 0.03-7.05 mM) in those given 4% lignocaine (p less than 0.01). The effect of increasing concentrations of lignocaine on BAL neutrophil and pulmonary macrophage metabolic activity, as assessed by latex-stimulated luminol- and lucigenin-amplified chemiluminescence (CL), respectively, in mixed BAL cell populations, were measured following preincubation of "washed" harvested BAL cells with 0.4-8.0 mM lignocaine. There was no demonstrable decline in either cell activity with lignocaine concentrations of up to 2 mM, with dose-dependent inhibition of both above this threshold. Cell viability was unaffected. In a further experiment, the inhibition induced by 8 mM lignocaine on both pulmonary macrophage (lucigenin-amplified CL of harvested BAL cells) and isolated peripheral blood neutrophil metabolic activity was completely reversed by a single "wash", following both 30 and 60 min incubations at 4 degrees C, which was equivalent to resuspending harvested BAL cells in fresh medium after separation from BAL supernatant.(ABSTRACT TRUNCATED AT 250 WORDS)
Long-Term Course of Patients With Stage IA Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the German Hodgkin Study Group
Authors: Dennis A. Eichenauer, Annette Plütschow, Michael Fuchs, Bastian von Tresckow, Boris Böll, Karolin Behringer, Volker Diehl, Hans Theodor Eich, Peter Borchmann, Andreas Engert
Journal: Journal of Clinical Oncology (2015)

The optimal treatment of stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is not well defined. Thus, we performed an analysis using the database of the German Hodgkin Study Group.The long-term outcome of 256 patients with stage IA NLPHL was evaluated. Patients had received combined-modality treatment (CMT; n = 72), extended-field radiotherapy (EF-RT; n = 49), involved-field radiotherapy (IF-RT; n = 108), or four weekly standard doses of rituximab (n = 27) within German Hodgkin Study Group clinical trial protocols between 1988 and 2009.The median age at NLPHL diagnosis was 39 years (range, 16 to 75 years). Most patients were male (76%). The whole patient group had a median follow-up of 91 months (CMT: 95 months; EF-RT: 110 months; IF-RT: 87 months; rituximab: 49 months). At 8 years, progression-free survival and overall survival rates were 88.5% and 98.6% for CMT, 84.3% and 95.7% for EF-RT, and 91.9% and 99.0% for IF-RT, respectively. Patients treated with rituximab had 4-year progression-free and overall survival rates of 81.0% and 100%, respectively. A second malignancy during the course of follow-up was diagnosed in 17 (6.6%) of 256 patients. A total of 12 deaths occurred. However, only one patient died from NLPHL.Tumor control in this analysis was equivalent with CMT, EF-RT, and IF-RT. Therefore, IF-RT, which is associated with the lowest risk for the development of toxic effects, should be considered as standard of care for patients with stage IA NLPHL. Rituximab alone is associated with an increased risk of relapse in this patient population.
Effects of DNA Methylation on Galectin-3 Expression in Pituitary Tumors
Authors: Katharina H. Ruebel, Long Jin, Xiang Qian, Bernd W. Scheithauer, Kalman Kovacs, Nobuki Nakamura, Heyu Zhang, Avraham Raz, Ricardo V. Lloyd
Journal: Cancer Research (2005)

Abstract Galectin-3 (Gal-3), a β-galactoside-binding protein is expressed in a specific cell–type manner in pituitary tumors. Here we questioned the mechanism of Gal-3 expression in pituitary tumors, by using methylation-specific PCR and DNA sequence analyses to analyze the methylation status of the promoter region of the LGALS3 gene. DNA analysis of a human pituitary tumor, breast carcinoma cell lines, and thyroid carcinoma cell lines showed that in cells expressing Gal-3 protein, the LGALS3 gene was unmethylated, whereas in Gal-3 null cells, the promoter of the LGALS3 gene was methylated. Treatment of cells with 30 μmol/L 5-aza-2′-deoxycytidine induced Gal-3 mRNA and protein expression. Among pituitary tumors, 30% (7/23), mainly in follicle-stimulating hormone/luteinizing hormone–producing (38%) and null cell (57%) adenomas, the promoter of the LGALS3 was found to be methylated and silenced, although prolactin- and adrenocorticotropic hormone–producing tumors, which were unmethylated, expressed the Gal-3 protein. These results show for the first time that Gal-3 expression is regulated in part by promoter methylation in pituitary as well as in other tumors. Because it is functionally involved in cancer progression and metastasis, Gal-3 may serve as a possible therapeutic target in the treatment of pituitary tumors.
Increased p53 gene dosage reduces neointimal thickening induced by mechanical injury but has no effect on native atherosclerosis
Authors: S SANZGONZALEZ, L BARQUIN, I GARCIACAO, M ROQUE, J GONZALEZ, J FUSTER, M CASTELLS, J FLORES, M SERRANO, V ANDRES
Journal: Cardiovascular Research (2007)

Objective The tumor suppressor p53 regulates cell proliferation and apoptosis, two key processes in the pathogenesis of occlusive vascular disease. Here, we examined the consequences of heightening p53 function on neointimal lesion formation in the setting of atherosclerosis and mechanical injury.
Importance of glycolysis and oxidative phosphorylation in advanced melanoma
Authors: Jonhan Ho, Michelle Barbi de Moura, Yan Lin, Garret Vincent, Stephen Thorne, Lyn M Duncan, Lin Hui-Min, John M Kirkwood, Dorothea Becker, Bennett Van Houten, Stergios J Moschos
Journal: Molecular Cancer (2012)

Serum lactate dehydrogenase (LDH) is a prognostic factor for patients with stage IV melanoma. To gain insights into the biology underlying this prognostic factor, we analyzed total serum LDH, serum LDH isoenzymes, and serum lactate in up to 49 patients with metastatic melanoma. Our data demonstrate that high serum LDH is associated with a significant increase in LDH isoenzymes 3 and 4, and a decrease in LDH isoenzymes 1 and 2. Since LDH isoenzymes play a role in both glycolysis and oxidative phosphorylation (OXPHOS), we subsequently determined using tissue microarray (TMA) analysis that the levels of proteins associated with mitochondrial function, lactate metabolism, and regulators of glycolysis were all elevated in advanced melanomas compared with nevic melanocytes. To investigate whether in advanced melanoma, the glycolysis and OXPHOS pathways might be linked, we determined expression of the monocarboxylate transporters (MCT) 1 and 4. Analysis of a nevus-to-melanoma progression TMA revealed that MCT4, and to a lesser extend MCT1, were elevated with progression to advanced melanoma. Further analysis of human melanoma specimens using the Seahorse XF24 extracellular flux analyzer indicated that metastatic melanoma tumors derived a large fraction of energy from OXPHOS. Taken together, these findings suggest that in stage IV melanomas with normal serum LDH, glycolysis and OXPHOS may provide metabolic symbiosis within the same tumor, whereas in stage IV melanomas with high serum LDH glycolysis is the principle source of energy.