tbuckley/cabot-search huggingface dataset:
Nox Activator 1
Authors: Xi-Lin Niu, Nageswara R. Madamanchi, Aleksandr E. Vendrov, Igor Tchivilev, Mauricio Rojas, Chaitanya Madamanchi, Ralph P. Brandes, Karl-Heinz Krause, Julia Humphries, Alberto Smith, Kevin G. Burnand, Marschall S. Runge
Journal: Circulation (2010)

Despite a concerted effort by many laboratories, the critical subunits that participate in vascular smooth muscle cell (VSMC) NADPH oxidase function have yet to be elucidated. Given the potential therapeutic importance of cell-specific inhibition of NADPH oxidase, we investigated the role of Nox activator 1 (NoxA1), a homolog of p67phox, in VSMC NADPH oxidase function and atherosclerosis.The presence of NoxA1 in mouse aortic VSMCs was confirmed by reverse-transcription polymerase chain reaction and sequencing. NoxA1/p47phox interaction after thrombin treatment was observed by immunoprecipitation/Western analysis of lysates from p47phox(-/-) VSMCs transfected with adenoviral HA-NoxA1 and Myc-p47phox. Infection with adenoviral NoxA1 significantly enhanced thrombin-induced reactive oxygen species generation in wild-type but not in p47phox(-/-) and Nox1(-/-) VSMCs. Thrombin-induced reactive oxygen species production and VSMC proliferation were significantly reduced after downregulation of NoxA1 with shRNA. Infection with NoxA1 shRNA but not scrambled shRNA significantly decreased thrombin-induced activation of the redox-sensitive protein kinases (Janus kinase 2, Akt, and p38 mitogen-activated protein kinase) in VSMCs. Adenovirus-mediated overexpression of NoxA1 in guidewire-injured mouse carotid arteries significantly increased superoxide production in medial VSMCs and enhanced neointimal hyperplasia. NoxA1 expression was significantly increased in aortas and atherosclerotic lesions of ApoE(-/-) mice compared with age-matched wild-type mice. Furthermore, in contrast to p67phox, immunoreactive NoxA1 is present in intimal and medial SMCs of human early carotid atherosclerotic lesions.NoxA1 is the functional homolog of p67phox in VSMCs that regulates redox signaling and VSMC phenotype. These findings support the potential for modulation of NoxA1 expression as a viable approach for the treatment of vascular diseases.
Risk disclosure prior to bronchoscopy
Authors: S. M. Bianchi, S. Saha, P. Anderson
Journal: Thorax (2010)

MRI in assessment of lung cancerWe congratulate Fischer et al for their significant and well-written article, published in this issue of Thorax. 1 The report covers important topics in the imaging of lung cancer staging.The authors report that positron emission tomography (PET)-CT improves discrimination in metastatic disease.They also demonstrated that patients with enlarged lymph nodes on CT require confirmation independent of PET findings, and that a positive PET-CT finding requires confirmation before making a decision about surgery.We would, however, like to discuss and highlight an alternative technique with benefits for lung cancer staging.Recent advancements in MRI systems (such as improved pulse sequences, utilisation of contrast media and new techniques such as diffusion) have made MRI an increasingly important tool for lung cancer staging.Reports have indicated the ability of MRI to reveal mediastinal tumour invasion and to help identify hilar and mediastinal nodal metastases.2e4 A series of 115 consecutive non-small cell lung carcinoma patients prospectively underwent CT, MRI and 18 F-fluorodeoxyglucose (FDG)-PET, as well as surgical and pathological examinations.The study reported that the quantitative sensitivity (90.1%) and accuracy (92.2%) of MRI were significantly higher than the quantitative and qualitative sensitivities (76.7% and 74.4%) and accuracies (83.5% and 82.6%) of co-registered FDG-PET/CT on a per patient basis (p<0.05). 4he cost of imaging studies is an important consideration.The nature and complexity of the imaging system and the requirement for continuous production of radiopharmaceutical products makes PET/ CT intrinsically more expensive than other imaging methods.The characteristics of MRI make it a safer modality than PET/CT.Unlike the ionising radiation used in CT, the powerful magnetic field and radiofrequency energy of MRI have not been shown to cause cancer or fetal abnormalities.It is important to note that although x-rays are known to cause cancer, the exact risk of developing cancer from CT scans or repeated CT examinations is unknown. 5We hope that this short comment may encourage investigators to use and study MRI as a new method that offers considerable benefits for lung cancer staging.
Imidazoline Receptors and Their Endogenous Ligands
Authors: S Regunathan, D J Reis
Journal: The Annual Review of Pharmacology and Toxicology (1996)

Imidazoline (I) receptors constitute a family of nonadrenergic high-affinity binding sites for clonidine, idazoxan, and allied drugs. One major subclass, the I1 receptors, whose subcellular distribution and signal transduction mechanisms are uncertain, partly mediates the central hypotensive actions of clonidine-like drugs. The I2 receptors, another subclass, are mitochondrial, not G protein coupled, and have diversified functions. Several endogenous ligands for I receptors, collectively termed clonidine-displacing substances (CDSs), have been detected in tissues and serum, but the structure of only one, agmatine (decarboxylated arginine), is known. Agmatine, widely distributed and bioactive, binds, like clonidine, to alpha 2-adrenergic and I receptors of all subclasses. The presence of agmatine and its biosynthetic enzyme in synaptosomes and specific neuronal pathways as well as serum suggests that it may be a novel neurotransmitter/hormone. Another CDS that binds to I receptors and to antibodies to imidazoline drugs has been detected, but its structure is unknown.
Residual Normality and the issue of language profiles in Williams syndrome
Authors: Csaba Pléh, Ágnes Lukács, Mihály Racsmány
Journal: Behavioral and Brain Sciences (2002)

One of the debated issues regarding Residual Normality (RN) is frequency sensitivity in Williams syndrome (WS). We present some data on frequency sensitivity in Hungarian WS subjects. Based on vocabulary measures, we suggest that instead of the across-the-board frequency insensitivity proposed by some, a higher frequency threshold characterizes these subjects’performance. Results from a category fluency task show that whereas frequency sensitivity in WS is in line with controls, error patterns imply a qualitatively distinct, looser categorical organization. Regarding the much-debated issue of morphological overgeneralizations, our data suggest that frequency sensitivity cuts across the divisions proposed by dual-process theories. In general, some of the frequency effects are the same as in typically developing populations, but with a delayed pattern. Frequency may be interpreted as supporting RN, but in WS it operates with higher thresholds that might be a general processing feature of WS individuals.
From β- to α-Proteobacteria: The Origin and Evolution of Rhizobial Nodulation Genes nodIJ
Authors: Seishiro Aoki, Motomi Ito, Wataru Iwasaki
Journal: Molecular Biology and Evolution (2013)

Although many α- and some β-proteobacterial species are symbiotic with legumes, the evolutionary origin of nitrogen-fixing nodulation remains unclear. We examined α- and β-proteobacteria whose genomes were sequenced using large-scale phylogenetic profiling and revealed the evolutionary origin of two nodulation genes. These genes, nodI and nodJ (nodIJ), play key roles in the secretion of Nod factors, which are recognized by legumes during nodulation. We found that only the nodulating β-proteobacteria, including the novel strains isolated in this study, possess both nodIJ and their paralogous genes (DRA-ATPase/permease genes). Contrary to the widely accepted scenario of the α-proteobacterial origin of rhizobia, our exhaustive phylogenetic analysis showed that the entire nodIJ clade is included in the clade of Burkholderiaceae DRA-ATPase/permease genes, that is, the nodIJ genes originated from gene duplication in a lineage of the β-proteobacterial family. After duplication, the evolutionary rates of nodIJ were significantly accelerated relative to those of homologous genes, which is consistent with their novel function in nodulation. The likelihood analyses suggest that this accelerated evolution is not associated with changes in either nonsynonymous/synonymous substitution rates or transition/transversion rates, but rather, in the GC content. Although the low GC content of the nodulation genes has been assumed to reflect past horizontal transfer events from donor rhizobial genomes with low GC content, no rhizobial genome with such low GC content has yet been found. Our results encourage a reconsideration of the origin of nodulation and suggest new perspectives on the role of the GC content of bacterial genes in functional adaptation.
Obesity in Cancer Survival
Authors: Niyati Parekh, Urmila Chandran, Elisa V. Bandera
Journal: Annual Review of Nutrition (2012)

Although obesity is a well-known risk factor for several cancers, its role on cancer survival is poorly understood. We conducted a systematic literature review to assess the current evidence evaluating the impact of body adiposity on the prognosis of the three most common obesity-related cancers: prostate, colorectal, and breast. We included 33 studies of breast cancer, six studies of prostate cancer, and eight studies of colo-rectal cancer. We note that the evidence overrepresents breast cancer survivorship research and is sparse for prostate and colorectal cancers. Overall, most studies support a relationship between body adiposity and site-specific mortality or cancer progression. However, most of the research was not specifically designed to study these outcomes and, therefore, several methodological issues should be considered before integrating their results to draw conclusions. Further research is urgently warranted to assess the long-term impact of obesity among the growing population of cancer survivors.
Enzymatic properties of native and N-ethylmaleimide-modified cardiac myosin from normal and thyrotoxic rabbits.
Authors: S K Banerjee, I L Flink, E Morkin
Journal: Circulation Research (1976)

Cardiac myosin from thyrotoxic animals (myosin-T) exhibits elevated Ca2+ -ATPase activity which is resistant to further stimulation by sulfhydryl modification. In the present study, we have compared the enzymatic properties of myosin-T with those of myosin from euthyroid rabbits (myosin-N) and the derivatives of myosin-T and myosin-N formed by blocking the most rapidly reacting class of thiols (SH1) with N-ethylmaleimide (NEM). Vmax for Ca2+ -ATPase of myosin-T was about 250% greater than myosin-N and was nearly the same as NEM-modified myosin-N. Values for the apparent Km of myosin-T and NEM-modified myosin-N were 200% greater than the value for unmodified myosin-N. Vmax and Km for K+ (EDTA)-ATPase activity of NEM-modified myosin-T and myosin-N were identical. The Ca2+ saturation, pH, and salt-dependency curves for the ATPase activity of myosin-T were parallel to the curves for myosin-N and differed from those for the NEM-modified myosins. Myosin-T exhibited an increased rate of hydrolysis of ATP, CTP, and UTP in both low (0.05m) and high (0.5m) KCl medium. NEM-modified myosin-N showed increased hydrolysis of ATP and CTP in low KCl medium and increased hydrolysis of ATP, CTP, and UTP in high KCl medium. These results support the hypothesis that the enzymatic behavior of myosin-T may be caused by an alteration in the active site near the SH, thiols. The unique enzymatic properties of myosin-T did not seem to be the result of a major change in structure. The electrophoretic pattern of light chains from myosin-T and myosin-N was the same in polyacrylamide gels containing either 8 M urea at pH 8.6 or sodium dodecyl sulfate. Also, myosin-T had a normal amino acid composition and lacked 3-methyl-histidine and hot acid-stable phosphate.
Hemorrhage and the products of fibrinogen digestion after intracoronary administration of streptokinase.
Authors: G C Timmis, V Gangadharan, R G Ramos, A M Hauser, D C Westveer, J Stewart, R Goodfliesh, S Gordon
Journal: Circulation (1984)

Hemorrhage was prospectively identified in 26 of 116 consecutive patients (23%) who were receiving intracoronary streptokinase for occlusive coronary thrombi producing infarction. Bleeding was not influenced by the dose of streptokinase or the method of cardiac catheterization. Before treatment, prothrombin time and partial thromboplastin time were normal in both bleeders and nonbleeders. Fibrinogen levels measured by bioassay after streptokinase (mean +/- SEM) were 62 +/- 29 mg/dl in patients with major bleeding, 111 +/- 26 mg/dl in patients with minor bleeding, and 109 +/- 13 mg/dl in nonbleeders (p = NS). The regression slope b calculated from poststreptokinase fibrinogen time-concentration data in 71 patients was 4.7 mg/dl/hr. However, mean fibrinogen concentrations calculated at sequential 5 hr intervals revealed no net regeneration for the first 20 hr after thrombolysis. The apparent fibrinogen regeneration rate was less than normal (31 mg/kg/day) for more than 10 hr but subsequently increased to 94 +/- 10 mg/kg/day by the second day. The initial apparent latency of fibrinogen regeneration paralleled the sharp rise in fibrinogen degradation products, which began to decline after 20 hr of treatment but remained elevated well into the second day. Because of their anticoagulant effects, these products may interfere with the fibrinogen assay, causing spuriously low results. Thus, whether the early delay in fibrinogen regeneration is real or simply a reflection of the effects of fibrinogen degradation products on the bioassay, it signals the time for caution in initiating systemic heparin therapy.
Predicting 6-Year Mortality Risk in Patients With Type 2 Diabetes
Authors: Brian J. Wells, Anil Jain, Susana Arrigain, Changhong Yu, Wayne A. Rosenkrans, Michael W. Kattan
Journal: Diabetes Care (2008)

OBJECTIVE—The objective of this study was to create a tool that predicts the risk of mortality in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS—This study was based on a cohort of 33,067 patients with type 2 diabetes identified in the Cleveland Clinic electronic health record (EHR) who were initially prescribed a single oral hypoglycemic agent between 1998 and 2006. Mortality was determined in the EHR and the Social Security Death Index. A Cox proportional hazards regression model was created using medication class and 20 other predictor variables chosen for their association with mortality. A prediction tool was created using the Cox model coefficients. The tool was internally validated using repeated, random subsets of the cohort, which were not used to create the prediction model. RESULTS—Follow-up in the cohort ranged from 1 day to 8.2 years (median 28.6 months), and 3,661 deaths were observed. The prediction tool had a concordance index (i.e., c statistic) of 0.752. CONCLUSIONS—We successfully created a tool that accurately predicts mortality risk in patients with type 2 diabetes. The incorporation of medications into mortality predictions in patients with type 2 diabetes should improve treatment decisions.
Deficiency of tumour necrosis factor-related apoptosis-inducing ligand exacerbates lung injury and fibrosis
Authors: Emmet E McGrath, Allan Lawrie, Helen M Marriott, Paul Mercer, Simon S Cross, Nadine Arnold, Vanessa Singleton, Alfred A R Thompson, Sarah R Walmsley, Stephen A Renshaw, Ian Sabroe, Rachel C Chambers, David H Dockrell, Moira K B Whyte
Journal: Thorax (2012)

<h3>Background</h3> The death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) shows considerable clinical promise as a therapeutic agent. TRAIL induces leukocyte apoptosis, reducing acute inflammatory responses in the lung. It is not known whether TRAIL modifies chronic lung injury or whether TRAIL has a role in human idiopathic pulmonary fibrosis (IPF). We therefore explored the capacity of TRAIL to modify chronic inflammatory lung injury and studied TRAIL expression in patients with IPF. <h3>Methods</h3> TRAIL<sup>−/−</sup> and wild-type mice were instilled with bleomycin and inflammation assessed at various time points by bronchoalveolar lavage and histology. Collagen deposition was measured by tissue hydroxyproline content. TRAIL expression in human IPF lung samples was assessed by immunohistochemistry and peripheral blood TRAIL measured by ELISA. <h3>Results</h3> TRAIL<sup>−/−</sup> mice had an exaggerated delayed inflammatory response to bleomycin, with increased neutrophil numbers (mean 3.19±0.8 wild type vs 11.5±5.4×10<sup>4</sup> TRAIL<sup>−/−</sup>, p&lt;0.0001), reduced neutrophil apoptosis (5.42±1.6% wild type vs 2.47±0.5% TRAIL<sup>−/−</sup>, p=0.0003) and increased collagen (3.45±0.2 wild type vs 5.8±1.3 mg TRAIL<sup>−/−</sup>, p=0.005). Immunohistochemical analysis showed induction of TRAIL in bleomycin-treated wild-type mice. Patients with IPF demonstrated lower levels of TRAIL expression than in control lung biopsies and their serum levels of TRAIL were significantly lower compared with matched controls (38.1±9.6 controls vs 32.3±7.2 pg/ml patients with IPF, p=0.002). <h3>Conclusion</h3> These data suggest TRAIL may exert beneficial, anti-inflammatory actions in chronic pulmonary inflammation in murine models and that these mechanisms may be compromised in human IPF.
Reasons for considering leaving UK medicine: questionnaire study of junior doctors' comments
Authors: P. J Moss
Journal: BMJ (2004)

To study the reasons given by junior doctors trained in the United Kingdom for considering leaving UK medicine.Analysis of replies to postal questionnaire surveys.United Kingdom.1326 doctors who qualified in 1999.Reasons for considering leaving.Of 1047 doctors who indicated that they would stay in medicine but not necessarily in the United Kingdom, 65% (682) gave reasons for leaving that concerned lifestyle, such as a preference for living outside the United Kingdom; 41% (433) gave reasons concerning working conditions in UK medicine; and 18% (184) gave positive work related reasons, such as wanting to work in developing countries. Of 279 doctors considering leaving medicine, 75% (210) cited working conditions, 23% (63) cited lifestyle reasons, and 9% (24) cited positive interests in a different career. Of the 169 doctors who said that they would probably or definitely leave the United Kingdom but remain in medicine, 78% (132) specified lifestyle reasons. Of the 42 who said that they would probably or definitely leave medicine, 67% (28) cited working conditions.The wish to work abroad, but to stay in medicine, was more common than the wish to leave medicine. The preference for a different lifestyle, particularly to live outside the United Kingdom, is not readily amenable to policy changes to the medical working environment. The smaller numbers of doctors who gave work experience as a reason for considering leaving medicine might be influenced to stay by improvements in working lives.
Modification of GATA-2 Transcriptional Activity in Endothelial Cells by the SUMO E3 Ligase PIASy
Authors: Tae-Hwa Chun, Hiroshi Itoh, Lalitha Subramanian, Jorge A. Iñiguez-Lluhí, Kazuwa Nakao
Journal: Circulation Research (2003)

GATA sequences are required for the optimal expression of endothelial cell-specific genes, including endothelin-1 (ET-1). We have identified PIASy in a search for new GATA-2 interacting proteins that can regulate GATA-2-mediated endothelial gene expression. Notably, among the cell populations comprising vascular walls, PIASy mRNA is selectively expressed in endothelial cells, and its expression can be regulated by angiogenic growth factors. We show that GATA-2 is covalently modified by small ubiquitin-like modifier (SUMO)-1 and -2 and that PIASy, through its E3 SUMO ligase activity, preferentially enhances the conjugation of SUMO-2 to GATA-2. Through a functional analysis, we demonstrate that PIASy potently suppresses the activity of the GATA-2-dependent human ET-1 promoter in endothelial cells. The suppressive effect of PIASy requires the GATA-binding site in the ET-1 promoter and depends on its interaction with GATA-2, which requires both N-terminal (amino acids 1-183) and C-terminal (amino acids 414-510) sequences in PIASy. We conclude that PIASy enhances the conjugation of SUMO-2 to GATA-2 and that the interaction of PIASy with GATA-2 can modulate GATA-mediated ET-1 transcription activity in endothelial cells through a RING-like domain-independent mechanism.
Clinical Utility of Fluorescent in situ Hybridization for the Surveillance of Bladder Cancer Patients Treated with Bacillus Calmette-Guérin Therapy
Authors: Lourdes Mengual, Mercedes Marín-Aguilera, María José Ribal, Moisès Burset, Humberto Villavicencio, Artur Oliver, Antonio Alcaraz
Journal: European Urology (2007)
Effect of treatments on the progression of COPD: report of a workshop held in Leuven, 11-12 March 2004
Authors: Marc Decramer, Rik Gosselink, P. Bartsch, Claes Göran Löfdahl, Walter Vincken, Richard Dekhuijzen, J. Vestbo, Romain Pauwels, Robert Naeije, T. Troosters
Journal: Thorax (2005)

During the last decade several long term studies of interventions in patients with COPD have been published. This review analyses the potential of these interventions to alter the progression of the condition. The only treatment that has unequivocally been shown to reduce the rate of decline in FEV<sub>1</sub> is smoking cessation. Active psychological intervention in combination with pharmacotherapy is required. Other treatments may have an effect on the rate of decline in FEV<sub>1</sub> but this appears to be very small, at most. Several treatments affect the exacerbation rate and therefore might affect the progression of the disease. Further studies are warranted to examine this effect.
Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes
Authors: Jianqiang Ding, Govardhana R. Yannam, Namita Roy-Chowdhury, Tunda Hidvegi, Hesham Basma, Stephen I. Rennard, Ronald J. Wong, Yesim Avsar, Chandan Guha, David H. Perlmutter, Ira J. Fox, Jayanta Roy-Chowdhury
Journal: Journal of Clinical Investigation (2011)

α1-Antitrypsin deficiency is an inherited condition that causes liver disease and emphysema. The normal function of this protein, which is synthesized by the liver, is to inhibit neutrophil elastase, a protease that degrades connective tissue of the lung. In the classical form of the disease, inefficient secretion of a mutant α1-antitrypsin protein (AAT-Z) results in its accumulation within hepatocytes and reduced protease inhibitor activity, resulting in liver injury and pulmonary emphysema. Because mutant protein accumulation increases hepatocyte cell stress, we investigated whether transplanted hepatocytes expressing wild-type AAT might have a competitive advantage relative to AAT-Z-expressing hepatocytes, using transgenic mice expressing human AAT-Z. Wild-type donor hepatocytes replaced 20%-98% of mutant host hepatocytes, and repopulation was accelerated by injection of an adenovector expressing hepatocyte growth factor. Spontaneous hepatic repopulation with engrafted hepatocytes occurred in the AAT-Z-expressing mice even in the absence of severe liver injury. Donor cells replaced both globule-containing and globule-devoid cells, indicating that both types of host hepatocytes display impaired proliferation relative to wild-type hepatocytes. These results suggest that wild-type hepatocyte transplantation may be therapeutic for AAT-Z liver disease and may provide an alternative to protein replacement for treating emphysema in AAT-ZZ individuals.