tbuckley/cabot-search huggingface dataset:
How much is too much? The treatment of mild asthma
Authors: P. M. O’Byrne
Journal: European Respiratory Journal (2007)

<h3>Abstract</h3> A set of putative novel small RNAs was recently identified as expressed in <i>Enterococcus faecium</i>, a major opportunistic pathogen involved in numerous healthcare-associated infections and hospital outbreaks. The aim of this study was to characterize the first functional analysis of one of them, <i>srn0030</i>, by phenotypic, genomic and transcriptomic approaches. By genomic analysis and RACE mapping, we revealed the presence of this RNA (previously designated as P<sub><i>tet</i></sub>) within the 5’-untrasnlated region (UTR) of <i>tet</i>(M), a gene conferring tetracycline resistance through ribosomal protection. The regulatory mechanism has previously been described as transcriptional attenuation, but has actually been poorly characterized. Hence, we provide original additional data, especially the presence of three upstream transcripts of ~100, ~150 and ~230 nt within the 5’-UTR of <i>tet</i>(M), suggesting an alternative regulatory mechanism. The total deletion of these three transcripts causes an unexpected decreasing of tetracycline resistance in <i>E. faecium</i>. The attenuation mechanism was investigated, and we confirmed that the transcriptional read-through and <i>tet</i>(M) overexpression induced by tetracycline addition but the function of putative peptide leader on attenuation mechanism was not supported by our data. We report here new phenotypic and transcriptomic observations in <i>E. faecium</i> demonstrating an alternative regulatory mechanism of <i>tet</i>(M) gene expression.
β-Catenin Regulates Multiple Steps of RNA Metabolism as Revealed by the RNA Aptamer in Colon Cancer Cells
Authors: Hee Kyu Lee, Ho Yoon Kwak, Jung Hur, In Ae Kim, Ji Sun Yang, Min Woo Park, Jaehoon Yu, Sunjoo Jeong
Journal: Cancer Research (2007)

Abstract Nuclear β-catenin forms a transcription complex with TCF-4, which is implicated in colon cancer development and progression. Recently, we and others have shown that β-catenin could be a regulator of RNA splicing and it also stabilizes the cyclooxygenase-2 (COX-2) mRNA. Here, we further explored the role of β-catenin in the RNA metabolism in colon cancer cells. To specifically modulate the subcellular functions of β-catenin, we expressed the RNA aptamer in the form of RNA intramers with unique cellular localizations. The nucleus-expressed RNA intramer proved to be effective in reducing the protein-protein interaction between β-catenin and TCF-4, thus shown to be a specific regulator of β-catenin–activated transcription. It could also regulate the alternative splicing of E1A minigene in diverse colon cancer cell lines. In addition, we tested whether β-catenin could stabilize any other mRNAs and found that cyclin D1 mRNA was also bound and stabilized by β-catenin. Significantly, the cytoplasm-expressed RNA intramer reverted the β-catenin–induced COX-2 and cyclin D1 mRNA stabilization. We show here that β-catenin regulated multiple steps of RNA metabolism in colon cancer cells and might be the protein factor coordinating RNA metabolism. We suggest that the RNA intramers could provide useful ways for inhibiting β-catenin–mediated transcription and RNA metabolism, which might further enhance the antitumorigenic effects of these molecules in colon cancer cells. [Cancer Res 2007;67(19):9315–20]
Beneficial effects of hydralazine in severe mitral regurgitation.
Authors: B H Greenberg, B M Massie, B H Brundage, E H Botvinick, W W Parmley, K Chatterjee
Journal: Circulation (1978)

The severity of mitral regurgitation is, in part, determined by aortic impedance to left ventricular outflow. Sodium nitroprusside acutely decreases regurgitant flow, but the importance of its dual vasodilating effects, the lowering of peripheral vascular resistance and increasing of venous capacitance, is unclear. We studied the hemodynamic response to intravenous hydralazine, which selectively acts on the arteriolar resistance bed, in 10 patients with severe mitral regurgitation. Hydralazine produced a 50% increase in forward stroke volume (22 +/- 2 to 33 +/- 3 ml/m2, P less than 0.001) and a 33% reduction in regurgitant stroke volume (40 +/- 6 to 27 +/- 6 ml/m2, P less than 0.001), with a resultant fall in pulmonary capillary wedge v wave and mean pressures. Unlike nitroprusside, it did not alter left ventricular end-diastolic volume or pressure. Oral hydralazine maintained this hemodynamic improvement for at least 48 hours and, in three patients, provided more sustained clinical improvement. We conclude that hydralazine, by virtue of its selective lowering of aortic impedance, reduces the amount of mitral regurgitation and thus may be a useful mode of interim or chronic therapy in selected patients.
High incidence of treatment-induced and vaccine-escape hepatitis B virus mutants among human immunodeficiency virus/hepatitis B-infected patients
Authors: Karine Lacombe, Anders Boyd, Fabien Lavocat, Christian Pichoud, Joel Gozlan, Patrick Miailhes, Caroline Lascoux-Combe, Guy Vernet, Pierre-Marie Girard, Fabien Zoulim
Journal: Hepatology (2013)

Anti–hepatitis B virus (HBV) nucleos(t)ides analogs (NA) exert selective pressures on polymerase ( pol ) and surface ( S ) genes, inducing treatment resistance and increasing the risk of vaccine escape mutants. The rate of emergence for these mutations is largely unknown in patients coinfected with human immunodeficiency virus (HIV) and HBV undergoing dual-active therapy. In a 3-year, repeat-sampling, prospective cohort study, HBV viral genome sequences of 171 HIV-HBV coinfected patients, presenting with HBV viremia for at least one visit, were analyzed every 12 months via DNA chip. Logistic and Cox proportional hazard models were used to determine risk factors specifically for S gene mutations at baseline and during follow-up, respectively. HBV-DNA levels &gt;190 IU/mL substantially decreased from 91.8% at inclusion to 40.3% at month 36 ( P &lt; 0.001), while lamivudine (LAM) or emtricitabine (FTC) use remained steady (71.9%) and tenofovir (TDF) use expanded (month 0, 17.5%; month 36, 66.7%; P &lt; 0.001). The largest increase of any mutation class was observed in l-nucleoside–associated pol gene/antiviral-associated S gene mutations (cumulative incidence at the end of follow-up, 17.5%) followed by alkyl phosphonate-associated pol -gene (7.4%), immune-associated S gene (specifically any amino acid change at positions s120/s145, 6.4%), and d-cyclopentane–associated pol -gene mutations (2.4%). Incidence of l-nucleoside–associated pol -gene/antiviral–associated S gene mutations was significantly associated with concomitant LAM therapy (adjusted hazard ratio [HR], 4.61; 95% confidence interval [CI], 1.36-15.56), but inversely associated with TDF use (adjusted HR/month, 0.94; 95% CI,0.89-0.98). Cumulative duration of TDF was significantly associated with a reduction in the occurrence of immune-associated S gene mutations (HR/month, 0.88; 95% CI, 0.79-0.98). No major liver-related complications (e.g., fulminant hepatitis, decompensated liver, and hepatocellular carcinoma) were observed in patients with incident mutations. Conclusion : Vaccine escape mutants selected by NA exposure were frequent and steadily increasing during follow-up. Although the high antiviral potency of TDF can mitigate incident mutations, other antiviral options are limited in this respect. The public health implications of their transmission need to be addressed. (Hepatology 2013;53:912–922)
Is There a Place for (Deceptive) Placebos Within Clinical Practice?
Authors: Amir Raz, Cory S. Harris, Veronica de Jong, Hillel Braude
Journal: The American Journal of Bioethics (2009)

Recent findings, including our unpublished data, suggest that placebo treatments remain a tool that many clinicians use regularly (Tilburt et al. 2008; Sherman and Hickner 2008; Nitzan and Lichtenb...
Antigen-unspecific B Cells and Lymphoid Dendritic Cells Both Show Extensive Surface Expression of Processed Antigen–Major Histocompatibility Complex Class II Complexes after Soluble Protein Exposure In Vivo or In Vitro
Authors: Guangming Zhong, Caetano Reis e Sousa, Ronald N. Germain
Journal: The Journal of Experimental Medicine (1997)

Intravenous (i.v.) injection of high amounts of soluble proteins often results in the induction of antigen-specific tolerance or deviation to helper rather than inflammatory T cell immunity. It has been proposed that this outcome may be due to antigen presentation to T cells by a large cohort of poorly costimulatory or IL-12–deficient resting B cells lacking specific immunoglobulin receptors for the protein. However, previous studies using T cell activation in vitro to assess antigen display have failed to support this idea, showing evidence of specific peptide–major histocompatibility complex (MHC) class II ligand only on purified dendritic cells (DC) or antigen-specific B cells isolated from protein injected mice. Here we reexamine this question using a recently derived monoclonal antibody specific for the T cell receptor (TCR) ligand formed by the association of the 46-61 determinant of hen egg lysozyme (HEL) and the mouse MHC class II molecule I-Ak. In striking contrast to conclusions drawn from indirect T cell activation studies, this direct method of TCR ligand analysis shows that i.v. administration of HEL protein results in nearly all B cells in lymphoid tissues having substantial levels of HEL 46-61–Ak complexes on their surface. DC readily isolated from spleen also display this TCR ligand on their surface. Although the absolute number of displayed ligands is greater on such DC, the relative specific ligand expression compared to total MHC class II levels is similar or greater on B cells. These results demonstrate that in the absence of activating stimuli, both lymphoid DC and antigen-unspecific B cells present to a similar extent class II–associated peptides derived from soluble proteins in extracellular fluid. The numerical advantage of the TCR ligand–bearing B cells may permit them to interact first or more often with naive antigen-specific T cells, contributing to the induction of high-dose T cell tolerance or immune deviation.
Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair
Authors: Giovanna Leoni, Ashfaqul Alam, Philipp-Alexander Neumann, J. David Lambeth, Guangjie Cheng, James McCoy, Roland S. Hilgarth, Kousik Kundu, Niren Murthy, Dennis Kusters, Chris Reutelingsperger, Mauro Perretti, Charles A. Parkos, Andrew S. Neish, Asma Nusrat
Journal: Journal of Clinical Investigation (2012)

N-formyl peptide receptors (FPRs) are critical regulators of host defense in phagocytes and are also expressed in epithelia. FPR signaling and function have been extensively studied in phagocytes, yet their functional biology in epithelia is poorly understood. We describe a novel intestinal epithelial FPR signaling pathway that is activated by an endogenous FPR ligand, annexin A1 (ANXA1), and its cleavage product Ac2-26, which mediate activation of ROS by an epithelial NADPH oxidase, NOX1. We show that epithelial cell migration was regulated by this signaling cascade through oxidative inactivation of the regulatory phosphatases PTEN and PTP-PEST, with consequent activation of focal adhesion kinase (FAK) and paxillin. In vivo studies using intestinal epithelial specific Nox1–/–IEC and AnxA1–/– mice demonstrated defects in intestinal mucosal wound repair, while systemic administration of ANXA1 promoted wound recovery in a NOX1-dependent fashion. Additionally, increased ANXA1 expression was observed in the intestinal epithelium and infiltrating leukocytes in the mucosa of ulcerative colitis patients compared with normal intestinal mucosa. Our findings delineate a novel epithelial FPR1/NOX1-dependent redox signaling pathway that promotes mucosal wound repair.
Brucellosis may Impair Endothelial Functions in Chronic Symptomatic Patients without Overt Cardiac Involvement
Authors: Mustafa Ozan Gürsoy, İrfan Tursun, Mehmet Alpua, Müge Tokat Çobanlı, Aslı Haykır Solay, Hale Demirtaş, Gülten Ercan, Semra Gürsoy, Süleyman Karakoyun, Mehmet Özkan
Journal: Journal of the American College of Cardiology (2013)
Dickkopf-1 Promotes Hyperglycemia–Induced Accumulation of Mesangial Matrix and Renal Dysfunction
Authors: Chun-Liang Lin, Jeng-Yi Wang, Jih-Yang Ko, Yu-Ting Huang, Yu-Hsia Kuo, Feng-Sheng Wang
Journal: Journal of the American Society of Nephrology (2009)

Wnt/beta-catenin signaling mediates renal fibrosis in several model systems including diabetic nephropathy. Dickkopf-1 (DKK-1) is an endogenous inhibitor of Wnt/beta-catenin signaling, but whether DKK-1 modulates diabetic nephropathy is unknown. Here, we studied whether DKK-1 participates in high glucose (HG)-induced expression of profibrotic factors and renal damage. In vitro, HG increased expression of DKK1, receptor Kremen-2, TGF-beta1, and fibronectin in mesangial cells. Loss and gain of DKK1 function modulated HG-mediated c-Jun, TGF-beta1, and fibronectin expression. DKK1 mediated HG-induced phosphorylation of Ser45-beta-catenin and reduction of nuclear beta-catenin levels, but not phosphorylation of ERK kinase. Wnt3a protein and the beta-catenin (Delta45) mutation increased nuclear beta-catenin but abrogated HG-induced DKK1 and fibronectin expression. Exogenous DKK1 antisense oligonucleotide attenuated the increase in both serum DKK1 and urinary protein excretion in streptozotocin-induced diabetic rats. Knocking down DKK1 inhibited mesangial expression of TGF-beta1 and fibronectin and reduced both the glomerular volume and deposition of mesangial matrix in diabetic kidneys. Taken together, DKK1 mediates HG-induced destabilization of beta-catenin and matrix accumulation in mesangial cells. Knocking down DKK1 prevents diabetes-induced renal dysfunction and microstructure deterioration, suggesting that inhibition of DKK1offers therapeutic potential for diabetic nephropathy.
Update on HIV resistance and resistance testing
Authors: Joseph Sebastian, Hawazin Faruki
Journal: Medicinal Research Reviews (2003)

The introduction of highly active antiretroviral therapy, including a combination of antivirals directed at various steps in the viral life cycle, has led to significant decreases in morbidity and mortality associated with human immunodeficiency virus (HIV-1) infections. Despite the availability of numerous antivirals, many extensively treated patients gradually loose the ability to control viral replication because of development of antiviral resistance. Laboratory tests have been developed and validated to assist in recognizing such resistance and to help predict which antivirals may be more likely to control viral replication in a given patient. Both genotypic and phenotypic assays have been developed to assess HIV-1 antiviral resistance. The assay methodologies, including the advantages and disadvantages of each method, as well as the limitations of each method are reviewed. The ability to predict likely drug response from a genotype or a phenotype is continually evolving, and the more recently discovered mutation/drug resistance associations are discussed in terms of their implications for HIV resistance assays. To provide additional options for those who have developed resistance to all currently available drugs, new antivirals, such as the fusion inhibitors, are being developed. These new classes of antivirals block the HIV viral life cycle at sites other than reverse transcriptase and protease. Unique and novel resistance assays are being developed to measure HIV resistance to these new drugs.
Physiological responses of the airway wall and lung in hyperresponsive pigs
Authors: D.J. Turner, P.R. Gray, S.A. Taylor, J. Thomas, H.W. Mitchell
Journal: European Respiratory Journal (2001)

Airway hyperresponsiveness (AHR) might be driven by mechanisms inherent to the airway wall, and/or by factors arising from outside the airways. A porcine model of allergen-induced AHR was utilized to investigate physiological responses in intact airways in vitro and their contribution to responsiveness in vivo . Responsiveness to acetylcholine (ACh) was measured in eight ovalbumin (OA)-sensitized/challenged pigs (tests) and eight saline-challenged controls. In vivo responsiveness to ACh was determined from pulmonary resistance ( R L ). In vitro responsiveness to ACh was determined from airway pressure in isovolumic bronchial segments, after exposure via the adventitial or the luminal surface. Test pigs had lung (255±26% increase in R L , p&lt;0.0001) and skin responses to OA, and AHR to ACh (p&lt;0.0001). In vitro , test bronchi were less sensitive than controls to ACh applied to the airway adventitia (negative log of the ACh concentration producing half the maximum response (pD 2 )=4.18 and 4.58 respectively, p&lt;0.01), but not the lumen. Test bronchi had an increased amount of smooth muscle normalized for airway size versus controls (p&lt;0.05). Maximum responses to lumenal ACh in vitro showed a weak positive correlation with maximum changes to ACh in vivo (r=0.599, p=0.05). This study concludes that the effect of antigen challenge on bronchial responsiveness varies with the route of exposure to acetylcholine. In vitro responses to lumenal acetylcholine are increased despite a possible reduction in responsiveness of airway smooth muscle. Responsiveness of the bronchial wall only partially explains responsiveness of the lungs in vivo .
Class III β-tubulin, but not ERCC1, is a strong predictive and prognostic marker in locally advanced head and neck squamous cell carcinoma
Authors: Y. Koh, T.M. Kim, Y.K. Jeon, T.-K. Kwon, J.H. Hah, S.-H. Lee, D.-W. Kim, H.-G. Wu, C.-S. Rhee, M.-W. Sung, C.W. Kim, K.H. Kim, D.S. Heo
Journal: Annals of Oncology (2009)
Increased expression of adhesion molecules (ICAM‐1 and LFA‐1) on alveolar macrophages from asthmatic patients
Authors: P. Chanez, A. M. Vignola, P. Lacoste, F. B. Michel, P. Godard, J. Bousquet
Journal: Allergy (1993)

In the airways inflammation observed in asthma, activated macrophages are present in increased numbers. Adhesion molecules are required for the cell: cell contacts between leukocytes and endothelial cells or other leukocytes, and they are induced by inflammatory stimuli. We studied the expression of two adhesion molecules (ICAM‐1 and LFA‐1) on alveolar macrophages recovered by bronchoalveolar lavage from 11 normal subjects and 13 asthmatic patients by using immunocytochemistry. Two specific monoclonal antibodies were used, and the reaction was revealed by the alkaline phosphatase‐antialkaline phosphatase (APAAP) method. The percentage of cells expressing ICAM‐1 or LFA‐1 was significantly increased in asthmatic patients, as compared with normal subjects ( P &lt; 0.001 and P &lt; 0.002, respectively; Mann‐Whitney U test), and there was a significant correlation with the percentage of cells expressing both markers in asthma ( P &lt; 0.03, Spearman rank test). This study highlights the importance of macrophages in the inflammation of asthma and suggests that macrophage interactions with other cells play a role in this inflammation.
Use of a Prognostic Treadmill Score in Identifying Diagnostic Coronary Disease Subgroups
Authors: Leslee J. Shaw, Eric D. Peterson, Linda K. Shaw, Karen L. Kesler, Elizabeth R. DeLong, Frank E. Harrell, Lawrence H. Muhlbaier, Daniel B. Mark
Journal: Circulation (1998)

Background —Exercise testing is useful in the assessment of symptomatic patients for diagnosis of significant or extensive coronary disease and to predict their future risk of cardiac events. The Duke treadmill score (DTS) is a composite index that was designed to provide survival estimates based on results from the exercise test, including ST-segment depression, chest pain, and exercise duration. However, its usefulness for providing diagnostic estimates has yet to be determined. Methods and Results —A logistic regression model was used to predict significant (≥75% stenosis) and severe (3-vessel or left main) coronary artery disease, and a Cox regression analysis was used to predict cardiac survival. After adjustment for baseline clinical risk, the DTS was effectively diagnostic for significant ( P &lt;0.0001) and severe ( P &lt;0.0001) coronary artery disease. For low-risk patients (score ≥+5), 60% had no coronary stenosis ≥75% and 16% had single-vessel ≥75% stenosis. By comparison, 74% of high-risk patients (score &lt;−11) had 3-vessel or left main coronary disease. Five-year mortality was 3%, 10%, and 35% for low-, moderate-, and high-risk DTS groups ( P &lt;0.0001). Conclusions —The composite DTS provides accurate diagnostic and prognostic information for the evaluation of symptomatic patients evaluated for clinically suspected ischemic heart disease.
Early Tumor Drug Pharmacokinetics Is Influenced by Tumor Perfusion but not Plasma Drug Exposure
Authors: Azeem Saleem, Pat M. Price
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Pharmacokinetic parameters derived from plasma sampling are used as a surrogate of tumor pharmacokinetics. However, pharmacokinetics-modulating strategies do not always result in increased therapeutic efficacy. Nonsurrogacy of plasma kinetics may be due to tissue-specific factors such as tumor perfusion. Experimental Design: To assess the impact of tumor perfusion and plasma drug exposure on tumor pharmacokinetics, positron emission tomography studies were done with oxygen-15 radiolabeled water in 12 patients, with 6 patients undergoing positron emission tomography studies with carbon-11 radiolabeled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide and the other 6 with fluorine-18 radiolabeled 5-fluorouracil. Results: We found that tumor blood flow (mL blood/mL tissue/minute) was significantly correlated to early tumor radiotracer uptake between 4 and 6 minutes [standard uptake value (SUV)4-6; ρ = 0.79; P = 0.002], tumor radiotracer exposure over 10 minutes [area under the time-activity curve (AUC)0-10; predominantly parent drug; ρ = 0.86; P &amp;lt; 0.001], and tumor radiotracer exposure over 60 minutes (AUC0-60; predominantly radiolabeled metabolites; ρ = 0.80; P = 0.002). Similarly, fractional volume of distribution of radiolabeled water in tumor (Vd) was significantly correlated with SUV4-6 (ρ = 0.80; P = 0.002), AUC0-10 (ρ = 0.85; P &amp;lt; 0.001), and AUC0-60 (ρ = 0.66; P = 0.02). In contrast, no correlation was observed between plasma drug or total radiotracer exposure over 60 minutes and tumor drug uptake or exposure. Tumor blood flow was significantly correlated to Vd (ρ = 0.69; P = 0.014), underlying the interdependence of tumor perfusion and Vd. Conclusions: Tumor perfusion is a key factor that influences tumor drug uptake/exposure. Tumor vasculature-targeting strategies may thus result in improved tumor drug exposure and therefore drug efficacy.
Quantification of HBsAg in nucleos(t)ide-naïve patients treated for chronic hepatitis B with entecavir with or without tenofovir in the BE-LOW study
Authors: Fabien Zoulim, Giampiero Carosi, Susan Greenbloom, Wlodzimierz Mazur, Tuan Nguyen, Lennox Jeffers, Maurizia Brunetto, Song Yu, Cyril Llamoso
Journal: Journal of Hepatology (2014)
Mechanisms of tumour vascularization in cutaneous malignant melanoma: clinical implications
Authors: I. Pastushenko, P.B. Vermeulen, G.G. Van den Eynden, A. Rutten, F.J. Carapeto, L.Y. Dirix, S. Van Laere
Journal: British Journal of Dermatology (2014)

Malignant melanoma represents < 10% of all skin cancers but is responsible for the majority of skin‐cancer‐related deaths. Metastatic melanoma has historically been considered as one of the most therapeutically challenging malignancies. Fortunately, for the first time after decades of basic research and clinical investigation, new drugs have produced major clinical responses. Angiogenesis has been considered an important target for cancer treatment. Initial efforts have focused primarily on targeting endothelial and tumour‐related vascular endothelial growth factor signalling. Here, we review different mechanisms of tumour vascularization described in melanoma and discuss the potential clinical implications.