tbuckley/cabot-search huggingface dataset:
Soluble CD14 participates in the response of cells to lipopolysaccharide.
Authors: E A Frey, D S Miller, T G Jahr, A Sundan, V Bazil, T Espevik, B B Finlay, S D Wright
Journal: The Journal of Experimental Medicine (1992)

CD14 is a 55-kD protein found both as a glycosylphosphatidyl inositol-linked protein on the surface of mononuclear phagocytes and as a soluble protein in the blood. CD14 on the cell membrane (mCD14) has been shown to serve as a receptor for complexes of lipopolysaccharide (LPS) with LPS binding protein, but a function for soluble CD14 (sCD14) has not been described. Here we show that sCD14 enables responses to LPS by cells that do not express CD14. We have examined induction of endothelial-leukocyte adhesion molecule 1 expression by human umbilical vein endothelial cells, interleukin 6 secretion by U373 astrocytoma cells, and cytotoxicity of bovine endothelial cells. None of these cell types express mCD14, yet all respond to LPS in a serum-dependent fashion, and all responses are completely blocked by anti-CD14 antibodies. Immunodepletion of sCD14 from serum prevents responses to LPS, and the responses are restored by addition of sCD14. These studies suggest that a surface anchor is not needed for the function of CD14 and further imply that sCD14 must bind to additional proteins on the cell surface to associate with the cell and transduce a signal. They also indicate that sCD14 may have an important role in potentiating responses to LPS in cells lacking mCD14.
Inhomogeneities of Ventilation and the Diffusing Capacity to Perfusion in Various Chronic Lung Diseases
Authors: KAZUHIRO YAMAGUCHI, MASAAKI MORI, AKIRA KAWAI, TOMOAKI TAKASUGI, YOSHITAKA OYAMADA, EIICHI KODA
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Although impairment of gas exchange caused by ventilation-perfusion (VA/Q) mismatch has been extensively analyzed, there have been no systematic studies focused on determining the distributions of diffusion properties in dose connection with those of VA/Q. We attempted to clarify the simultaneous distributions of VA/Q and diffusion capacity to perfusion (D/Q) in patients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD). To assess pathologic determinants causing functional abnormalities, we compared VA/Q and D/Q distributions with the findings on high-resolution computed tomography. O2, CO2, and CO together with six foreign inert gases were used as indicator gases. We transformed the measured data on indicator gases in arterial blood into a continuous distribution of Q in the VA/Q-D/Q field. In IPF, active alveolitis or acinitis played a major role in producing low D/Q regions impeding gas exchange via a diffusion limitation, whereas extensive fibrosis with minimal inflammation accounted for low D/Q as well as low VA/Q regions. In COPD, no regions with low D/Q ratios were observed, but an abnormality in the VA/Q distribution with low or high VA/Q ratios was identified. Emphysematous lesions produced high VA/Q regions, whereas peripheral airway involvement yielded low VA/Q regions. These findings suggest that hypoxemia in patients with IPF is caused by inhomogeneous distributions of D/Q in combination with those of VA/Q. Hypoxemia in patients with COPD is attributable primarily to inhomogeneities in VA/Q rather than in D/Q distributions.
Vasodilator-Stimulated Phosphoprotein Serine 239 Phosphorylation as a Sensitive Monitor of Defective Nitric Oxide/cGMP Signaling and Endothelial Dysfunction
Authors: Matthias Oelze, Hanke Mollnau, Nina Hoffmann, Ascan Warnholtz, Martin Bodenschatz, Albert Smolenski, Ulrich Walter, Mikhail Skatchkov, Thomas Meinertz, Thomas Münzel
Journal: Circulation Research (2000)

Abstract —Studies with cGMP-dependent protein kinase I (cGK-I)-deficient human cells and mice demonstrated that cGK-I ablation completely disrupts the NO/cGMP pathway in vascular tissue, which indicates a key role of this protein kinase as a mediator of the NO/cGMP action. Analysis of the vasodilator-stimulated phosphoprotein phosphorylated at serine 239 (P-VASP) is a useful tool to monitor cGK-I activation in platelets and cultured endothelial and smooth muscle cells. Therefore, we investigated whether endothelial dysfunction and/or vascular NO bioavailability is reflected by decreased vessel wall P-VASP and whether improvement of endothelial dysfunction restores this P-VASP. Incubation of aortic tissue from New Zealand White Rabbits with the NOS inhibitor N G -nitro- l d-arginine and endothelial removal strikingly reduced P-VASP. Oxidative stress induced by inhibition of CuZn superoxide dismutase increased superoxide and decreased P-VASP. Endothelial dysfunction in hyperlipidemic Watanabe rabbits (WHHL) was associated with increased vascular superoxide and with decreased P-VASP. Treatment of WHHL with AT 1 receptor blockade improved endothelial dysfunction, reduced vascular superoxide, increased vascular NO bioavailability, and increased P-VASP. Therefore, the level of vessel P-VASP closely follows changes in endothelial function and vascular oxidative stress. P-VASP is suggested to represent a novel biochemical marker for monitoring the NO-stimulated sGC/cGK-I pathway and endothelial integrity in vascular tissue.
Advances in Targeting IKK and IKK-Related Kinases for Cancer Therapy
Authors: Dung-Fang Lee, Mien-Chie Hung
Journal: Clinical Cancer Research (2008)

IkappaB kinases (IKK) and IKK-related kinases play critical roles in regulating the immune response through nuclear factor-kappaB and IFN regulatory factor-dependent signaling transduction cascades. Recently, these kinases have been implicated in the pathogenesis of many human diseases, including cancer. In fact, dysregulation of IKK activities promotes tumor survival, proliferation, migration, metastasis, and angiogenesis-common characteristics of many types of human cancers. Because of their oncogenic effects in human cancer development, targeting IKK and IKK-related kinases is becoming an increasingly popular avenue for the development of novel therapeutic interventions for cancer. This review will briefly cover the recent discovery of the downstream substrates of IKK and IKK-related kinases, and outline the strategies used for targeting IKK as a therapeutic intervention for cancer.
Adenosine-to-Inosine RNA Editing Mediated by ADARs in Esophageal Squamous Cell Carcinoma
Authors: Yan-Ru Qin, Jun-Jing Qiao, Tim Hon Man Chan, Ying-Hui Zhu, Fang-Fang Li, Haibo Liu, Jing Fei, Yan Li, Xin-Yuan Guan, Leilei Chen
Journal: Cancer Research (2013)

Abstract Esophageal squamous cell carcinoma (ESCC), the major histologic form of esophageal cancer, is a heterogeneous tumor displaying a complex variety of genetic and epigenetic changes. Aberrant RNA editing of adenosine-to-inosine (A-to-I), as it is catalyzed by adenosine deaminases acting on RNA (ADAR), represents a common posttranscriptional modification in certain human diseases. In this study, we investigated the status and role of ADARs and altered A-to-I RNA editing in ESCC tumorigenesis. Among the three ADAR enzymes expressed in human cells, only ADAR1 was overexpressed in primary ESCC tumors. ADAR1 overexpression was due to gene amplification. Patients with ESCC with tumoral overexpression of ADAR1 displayed a poor prognosis. In vitro and in vivo functional assays established that ADAR1 functions as an oncogene during ESCC progression. Differential expression of ADAR1 resulted in altered gene-specific editing activities, as reflected by hyperediting of FLNB and AZIN1 messages in primary ESCC. Notably, the edited form of AZIN1 conferred a gain-of-function phenotype associated with aggressive tumor behavior. Our findings reveal that altered gene-specific A-to-I editing events mediated by ADAR1 drive the development of ESCC, with potential implications in diagnosis, prognosis, and treatment of this disease. Cancer Res; 74(3); 840–51. ©2013 AACR.
TRAF3 regulates the effector function of regulatory T cells and humoral immune responses
Authors: Jae-Hoon Chang, Hongbo Hu, Jin Jin, Nahum Puebla-Osorio, Yichuan Xiao, Brian E. Gilbert, Robert Brink, Stephen E. Ullrich, Shao-Cong Sun
Journal: The Journal of Experimental Medicine (2013)

Regulatory T cells (Treg cells) control different aspects of immune responses, but how the effector functions of Treg cells are regulated is incompletely understood. Here we identified TNF receptor–associated factor 3 (TRAF3) as a regulator of Treg cell function. Treg cell–specific ablation of TRAF3 impaired CD4 T cell homeostasis, characterized by an increase in the Th1 type of effector/memory T cells. Moreover, the ablation of TRAF3 in Treg cells resulted in increased antigen-stimulated activation of follicular T helper cells (TFH cells), coupled with heightened formation of germinal centers and production of high-affinity IgG antibodies. Although the loss of TRAF3 did not reduce the overall frequency of Treg cells, it attenuated the antigen-stimulated production of follicular Treg cells (TFR cells). TRAF3 signaling in Treg cells was required to maintain high level expression of inducible co-stimulator (ICOS), which in turn was required for TFR cell generation and inhibition of antibody responses. These findings establish TRAF3 as a mediator of Treg cell function in the regulation of antibody responses and suggest a role for TRAF3 in mediating ICOS expression in Treg cells.
STUDIES ON BACTERIAL NUTRITION
Authors: Theodor Thjötta, O. T. Avery
Journal: The Journal of Experimental Medicine (1921)

The hemophilic bacteria of which Bacillus influenzae serves as a type require for their growth two distinct and separable substances, both of which are present in blood and neither of which alone suffices. These substances are (a) a vitamine-like substance which can be extracted from red blood corpuscles, from yeast, and from vegetable cells, which is relatively heat-labile and absorbed from solution by certain agents; (b) a so called X substance which is present in red blood cells, is heat-stable, and acts in minute amounts.
Atypical Measles 14 Years After Immunization
Authors: Erwin J. Haas
Journal: JAMA (1976)

ATYPICAL measles is a term used to describe the bizarre clinical manifestations of natural measles infection in children who previously received killed measles virus vaccine.<sup>1</sup>The syndrome consists of a two- to three-day prodrome of fever, headache, malaise, and cough, followed by a maculopapular rash that begins on the wrists and ankles. The rash has vesicular, urticarial, and petechial components; spreads to involve the palms, soles, and trunk; and fades after approximately one week. Peripheral edema and roentgenographic evidence of pneumonitis occur in all children reported. In about one half, pleural effusions develop. The white blood cell and differential cell counts are variable. A similar but less severe illness develops in those immunized with attenuated measles vaccine.<sup>2</sup> The following case shows that atypical measles can be seen many years after immunization. Postinfectious arthralgias may be part of the syndrome. <h3>Report of a Case</h3> In a previously well 17-year-old
Clinical, Histopathologic, and Molecular Markers of Prognosis: Toward a New Disease Risk Stratification System for Medulloblastoma
Authors: Amar Gajjar, Roberto Hernan, Mehmet Kocak, Christine Fuller, Youngsoo Lee, Peter J. McKinnon, Dana Wallace, Ching Lau, Murali Chintagumpala, David M. Ashley, Stewart J. Kellie, Larry Kun, Richard J. Gilbertson
Journal: Journal of Clinical Oncology (2004)

To assess the feasibility of performing central molecular analyses of fresh medulloblastomas obtained from multiple institutions and using these data to identify prognostic markers for contemporaneously treated patients.Ninety-seven samples of medulloblastoma were collected. Tumor content in samples was judged by frozen section review. Tumor ERBB2 protein and MYCC, MYCN, and TRKC mRNA levels were measured blind to clinical details using Western blotting and real-time polymerase chain reaction, respectively. Histopathologic and clinical review of each case was also performed. All data were subjected to independent statistical analysis.Sample acquisition and analysis times ranged from 3 to 6 days. Eighty-six samples contained sufficient tumor for analysis, including 38 classic, 30 nodular desmoplastic, and 18 large-cell anaplastic (LCA) medulloblastomas. Protein and mRNA were extracted from 81 and 49 tumors, respectively. ERBB2 was detected in 40% (n=32 of 81) of tumors, most frequently in LCA disease (P=.005), and was independently associated with a poor prognosis (P=.031). A combination of clinical characteristics and ERBB2 expression provided a highly accurate means of discriminating disease risk. One hundred percent (n=26) of children with clinical average-risk, ERBB2-negative disease were alive at 5 years, with a median follow-up of 5.6 years, compared with only 54% for children with average-risk, ERBB2-positive tumors (n=13; P=.0001). TRKC, MYCC, and MYCN expression and histopathologic subtype were not associated with prognosis in this study.Central and rapid molecular analysis of frozen medulloblastomas collected from multiple institutions is feasible. ERBB2 expression and clinical risk factors together constitute a highly accurate disease risk stratification tool.
Androgen-Induced Differentiation and Tumorigenicity of Human Prostate Epithelial Cells
Authors: Raanan Berger, Phillip G. Febbo, Pradip K. Majumder, Jean J. Zhao, Shayan Mukherjee, Sabina Signoretti, K. Thirza Campbell, William R. Sellers, Thomas M. Roberts, Massimo Loda, Todd R. Golub, William C. Hahn
Journal: Cancer Research (2004)

Abstract Androgen ablation is the primary treatment modality for patients with metastatic prostate cancer; however, the role of androgen receptor signaling in prostate cancer development remains enigmatic. Using a series of genetically defined immortalized and tumorigenic human prostate epithelial cells, we found that introduction of the androgen receptor induced differentiation of transformed prostate epithelial cells to a luminal phenotype reminiscent of organ-confined prostate cancer when placed in the prostate microenvironment. Moreover, androgen receptor expression converted previously androgen-independent, tumorigenic prostate epithelial cells into cells dependent on testosterone for tumor formation. These observations indicate that androgen receptor expression is oncogenic and addictive for the human prostate epithelium.
Quo Vadis With Targeted Drugs in the 21st Century?
Authors: Jonas Bergh
Journal: Journal of Clinical Oncology (2008)

Duringthelastfewdecades,arapiddevelopmenthastakenplace in the exploration and development of cancer drugs, including cytostatics,endocrineagents(firstgenerationoftargeteddrugs),andmore recently, a new generation of targeted drugs. This development was facilitated by a marked increase in knowledge on how to best run well-designed clinical studies within academic collaborative groups, mainlyintheUnitedStatesandEuropeandfrequentlywiththepharmaceutical industry as sponsors for the studies. Theaimswereandstillaretoregisterandestablishnewdrugsand indications for broad groups of patients based on conventional morphologic classification systems of the primary cancers. The inclusion criteria are frequently aimed at defining a clinically homogeneous patient population, although the interpatient molecular signatures may be markedly different between patients included, not investigated, and not detected. More recent studies have had large sample sizestobeabletodetectsmalldifferences.Anotherwaytoexpressthis is that a positive effect in few patients will be recorded as a statistically
Self-Protection by Cardiac Myocytes Against Hypoxia and Hyperoxia
Authors: Saul Winegrad, Daniel Henrion, Lydie Rappaport, Jane Lise Samuel
Journal: Circulation Research (1999)

Cardiac muscle must maintain a continuous balance between its energy supply and work performed. An important mechanism involved in achievement of this balance is cross talk via chemical signals between cardiac myocytes and the cardiac muscle vascular system. This has been demonstrated by incubating isolated cardiac myocytes in different concentrations of oxygen and then assaying the conditioned media for vasoactive substances on isolated aortic rings and small-resistance arteries. With increasing oxygen concentrations above 6%, cardiac myocytes produce increasing amounts of angiotensin I, which is converted to angiotensin II by the blood vessel. The angiotensin II stimulates vascular endothelial cells to secrete endothelin and increase vascular tone. Below 6% oxygen, cardiac myocytes secrete adenosine, which acts directly on vascular smooth muscle to block the effect of alpha-adrenergic agonists and reduce vascular tone. In an intact heart, the net effect of these 2 regulatory systems would be the maintenance of oxygen concentration within a narrow range at the cardiac myocytes. By acting as oxygen sensors, cardiac myocytes modulate vascular tone according to the needs of the myocytes and reduce potential problems of hypoxia and extensive formation of reactive oxygen species.
Bronchiolitis obliterans organizing pneumonia in an AIDS patient
Authors: N J Sanito, T F Morley, D V Condoluci
Journal: European Respiratory Journal (1995)

We present a case of bronchiolitis obliterans organizing pneumonia in a patient with acquired immune deficiency syndrome. Only three cases have previously been reported in patients infected with human immunodeficiency virus. In these four cases, bronchiolitis obliterans organizing pneumonia was similar in presentation, radiographic features and clinical course to that occurring in patients not infected with human immunodeficiency virus.
Late dominance of the inflammatory process in murine influenza by gamma/delta + T cells.
Authors: S R Carding, W Allan, S Kyes, A Hayday, K Bottomly, P C Doherty
Journal: The Journal of Experimental Medicine (1990)

The inflammatory response in the lungs of mice infected with an influenza A virus consists largely of macrophages and CD3+ T cells. Most T lymphocytes recovered before day 7 after infection express mRNA for the T cell receptor alpha/beta (TCR-alpha/beta), while TCR-gamma/delta mRNA+ cells are found at much higher frequency over the next 7 d. The predominant surface phenotype for the TCR-gamma/delta mRNA+ population is CD3+4-8-TCR-alpha/beta-. Some lymphocytes expressing all the known V gamma genes are found in the inflammatory exudate, but V gamma 2+/V gamma 1+ and V gamma 4+ T cells are present at highest frequency. The response is staged, with maximal numbers of V gamma 4+ cells occurring on day 10 after infection, while the predominant phenotype on day 13 is V gamma 2/V gamma 1+. The emerging peak in numbers of V gamma 4+ lymphocytes is paralleled by increasing numbers of macrophages expressing hsp mRNA. The later maxima found for the V gamma 2+/V gamma 1+ T cells is consistent with the possibility that at least some of these lymphocytes are responding to the hsp+ cells and are functioning to resolve the inflammatory process.
AMPKα1 controls hepatocyte proliferation independently of energy balance by regulating Cyclin A2 expression
Authors: Grégory Merlen, Géraldine Gentric, Séverine Celton-Morizur, Marc Foretz, Jacques-Emmanuel Guidotti, Véronique Fauveau, Jocelyne Leclerc, Benoit Viollet, Chantal Desdouets
Journal: Journal of Hepatology (2013)
Air travel and chronic obstructive pulmonary disease: a new algorithm for pre-flight evaluation
Authors: Anne Edvardsen, Aina Akerø, Carl C Christensen, Morten Ryg, Ole H Skjønsberg
Journal: Thorax (2012)

<h3>Background</h3> The reduced pressure in the aircraft cabin may cause significant hypoxaemia and respiratory distress in patients with chronic obstructive pulmonary disease (COPD). Simple and reliable methods for predicting the need for supplemental oxygen during air travel have been requested. <h3>Objective</h3> To construct a pre-flight evaluation algorithm for patients with COPD. <h3>Methods</h3> In this prospective, cross-sectional study of 100 patients with COPD referred to hypoxia-altitude simulation test (HAST), sea level pulse oximetry at rest (SpO<sub>2 SL</sub>) and exercise desaturation (SpO<sub>2 6MWT</sub>) were used to evaluate whether the patient is fit to fly without further assessment, needs further evaluation with HAST or should receive in-flight supplemental oxygen without further evaluation. HAST was used as the reference method. <h3>Results</h3> An algorithm was constructed using a combination of SpO<sub>2 SL</sub> and SpO<sub>2 6MWT</sub>. Categories for SpO<sub>2 SL</sub> were &gt;95%, 92–95% and &lt;92%, the cut-off value for SpO<sub>2 6MWT</sub> was calculated as 84%. Arterial oxygen pressure (PaO<sub>2 HAST</sub>) &lt;6.6 kPa was the criterion for recommending supplemental oxygen. This algorithm had a sensitivity of 100% and a specificity of 80% when tested prospectively on an independent sample of patients with COPD (n=50). Patients with SpO<sub>2 SL</sub> &gt;95% combined with SpO<sub>2 6MWT</sub> ≥84% may travel by air without further assessment. In-flight supplemental oxygen is recommended if SpO<sub>2 SL</sub>=92–95% combined with SpO<sub>2 6MWT</sub> &lt;84% or if SpO<sub>2 SL</sub> &lt;92%. Otherwise, HAST should be performed. <h3>Conclusions</h3> The presented algorithm is simple and appears to be a reliable tool for pre-flight evaluation of patients with COPD.
Rapid and short-acting mealtime insulin secretion with nateglinide controls both prandial and mean glycemia.
Authors: M Hanefeld, K P Bouter, S Dickinson, C Guitard
Journal: Diabetes Care (2000)

The objective of the study was to assess the efficacy and safety of four fixed doses of nateglinide compared with placebo in the treatment of patients with type 2 diabetes with focus on the prandial state.This randomized double-blind placebo-controlled multicenter study was conducted in 289 patients who received either nateglinide at doses of 30 mg (n = 51), 60 mg (n = 58), 120 mg (n = 63), or 180 mg (n = 57) or placebo (n = 60) before three main meals for 12 weeks. Levels of HbA1c, fasting plasma glucose (FPG), fructosamine, and plasma lipids were measured at predetermined intervals, and the effects of nateglinide on prandial glucose insulin, C-peptide, and triglyceride levels were measured after a liquid standard meal (Sustacal; Mead Johnson, Evansville, IN). Adverse events and hypoglycemic episodes were recorded.After a liquid meal challenge, nateglinide rapidly increased mealtime insulin levels within 30 min of drug intake and reduced mealtime glucose excursions without affecting triglyceride levels. At study end point, reduction of HbA1c levels was statistically significantly greater with nateglinide at doses of 60, 120, and 180 mg than placebo (-0.45, -0.62, and -0.64%, respectively; P<0.05). The mean level of FPG was significantly reduced versus placebo in the nateglinide 120-mg group only (-1.14 mmol/l P<0.01). Overall, nateglinide was well tolerated.This study demonstrated that nateglinide improves mealtime and mean glycemic control in a dose-dependent manner by restoring early insulin secretion phase. Nateglinide was well tolerated and is suitable for the treatment of patients with type 2 diabetes.