tbuckley/cabot-search huggingface dataset:
Tumour necrosis factor converting enzyme (TACE) activity in the colonic mucosa of patients with inflammatory bowel disease
Authors: J Brynskov, P Foegh, G Pedersen, C Ellervik, T Kirkegaard, A Bingham, T Saermark
Journal: Gut (2002)

<b>Background:</b> Anti-tumour necrosis factor α (TNF-α) antibodies are effective in Crohn9s disease and perhaps ulcerative colitis but antigenicity and the high cost have raised interest in other strategies to block TNF-α. These include the TNF-α converting enzyme (TACE) which releases soluble TNF-α from transmembrane pro-TNF-α. <b>Aim:</b> To investigate whether TACE activity is present in human colonic mucosa. <b>Materials and methods:</b> Detergent extracts of cell membranes from colonic biopsies were obtained from 12 controls and 28 patients with inflammatory bowel disease. Enzyme activity was measured by hydrolysis assays using pro-TNF-α or oligopeptide substrates spanning the known pro-TNF-α cleavage site at Ala(76)-Val(77). Cleavage products were identified by western blotting, high pressure liquid chromatography, or mass spectrometry. TACE protein was localised by immunohistochemistry and identified by western blotting of detergent extracts from purified lamina propria mononuclear cells (LPMNC) or epithelial cells. <b>Results:</b> Detergent extracts released TNF-α from pro-TNF-α and cleaved a model oligopeptide as predicted. Substrate hydrolysis was sensitive to known TACE/matrix metalloproteinase (MMP) inhibitors, but not trocade which has low activity against TACE. The median TACE level was increased in active ulcerative colitis (147 arbitrary units (AU)/mg; p&lt;0.01) but not in Crohn9s disease (81 AU/mg) compared with controls (79 AU/mg). Both the full length proform and the active form of TACE protein were expressed in LPMNC cells and epithelial cells. <b>Conclusions:</b> Functional TACE activity is ubiquitously expressed in the human colon and increased in ulcerative colitis, raising interest in MMP inhibitors targeting TACE.
Transcriptional Signatures of Ral GTPase Are Associated with Aggressive Clinicopathologic Characteristics in Human Cancer
Authors: Steven C. Smith, Alexander S. Baras, Charles R. Owens, Garrett Dancik, Dan Theodorescu
Journal: Cancer Research (2012)

RalA and RalB are small GTPases that support malignant development and progression in experimental models of bladder, prostate, and squamous cancer. However, demonstration of their clinical relevance in human tumors remains lacking. Here, we developed tools to evaluate Ral protein expression, activation, and transcriptional output and evaluated their association with clinicopathologic parameters in common human tumor types. To evaluate the relevance of Ral activation and transcriptional output, we correlated RalA and RalB activation with the mutational status of key human bladder cancer genes. We also identified and evaluated a transcriptional signature of genes that correlates with depletion of RalA and RalB in vivo. The Ral transcriptional signature score, but not protein expression as evaluated by immunohistochemistry, predicted disease stage, progression to muscle invasion, and survival in human bladder cancers and metastatic and stem cell phenotypes in bladder cancer models. In prostate cancer, the Ral transcriptional signature score was associated with seminal vesicle invasion, androgen-independent progression, and reduced survival. In squamous cell carcinoma, this score was decreased in cancer tissues compared with normal mucosa, validating the experimental findings that Ral acts as a tumor suppressor in this tumor type. Together, our findings show the clinical relevance of Ral in human cancer and provide a rationale for the development of Ral-directed therapies.
Macrophage plasminogen activator: induction by asbestos is blocked by anti-inflammatory steroids.
Authors: J Hamilton, J D Vassalli, E Reich
Journal: The Journal of Experimental Medicine (1976)

Intraperitoneal injection of asbestos fibres into mice induces the formation of exudates containing macrophages that produce plasminogen activator. Like-wise, in vitro addition of asbestos to macrophage cultures stimulates plasminogen activator secretion; the synthesis and secretion of lysozyme and lysosomal enzymes are not changed under these conditions. The enhanced secretion of plasminogen activator by macrophages exposed to asbestos is suppressed by low concentrations of anti-inflammatory steroids.
Toward transcriptional therapies for the failing heart: chemical screens to modulate genes
Authors: Timothy A. McKinsey, Eric N. Olson
Journal: Journal of Clinical Investigation (2005)

In response to acute and chronic stresses, the heart frequently undergoes a remodeling process that is accompanied by myocyte hypertrophy, impaired contractility, and pump failure, often culminating in sudden death. The existence of redundant signaling pathways that trigger heart failure poses challenges for therapeutic intervention. Cardiac remodeling is associated with the activation of a pathological gene program that weakens cardiac performance. Thus, targeting the disease process at the level of gene expression represents a potentially powerful therapeutic approach. In this review, we describe strategies for normalizing gene expression in the failing heart with small molecules that control signal transduction pathways directed at transcription factors and associated chromatin-modifying enzymes.
Angiopoietin 1 and Vascular Endothelial Growth Factor Modulate Human Glomerular Endothelial Cell Barrier Properties
Authors: Simon C. Satchell, Karen L. Anderson, Peter W. Mathieson
Journal: Journal of the American Society of Nephrology (2004)

Normal glomerular filtration depends on the combined properties of the three layers of glomerular capillary wall: glomerular endothelial cells (GEnC), basement membrane, and podocytes. Podocytes produce endothelial factors, including angiopoietin 1 (ang1), and vascular endothelial growth factor (VEGF), whereas GEnC express their respective receptors Tie2 and VEGFR2 in vivo. As ang1 acts to maintain the endothelium in other vascular beds, regulating some actions of VEGF, these observations suggest a mechanism whereby podocytes may direct the unique properties of the glomerular endothelium. This interaction was investigated by studies on the barrier properties of human GEnC in vitro. GEnC were examined for expression of endothelium-specific markers by immunofluorescence and Western blotting and for typical responses to TNF-alpha by a cell-based immunoassay. Expression of angiopoietin and VEGF receptors was examined similarly. Barrier properties of GEnC monolayers cultured on porous supports were investigated by measurement of transendothelial electrical resistance (TEER) and passage of labeled albumin. Responses to a cAMP analogue and thrombin were examined before those to ang1 and VEGF. Results confirmed the endothelial origin of GEnC and their expression of Tie2 and VEGFR2. GEnC formed monolayers with a mean TEER of 30 to 40 Omega/cm(2). The cAMP analogue and thrombin increased and decreased TEER by 34.4 and 14.8 Omega/cm(2), respectively, with corresponding effects on protein passage. Ang1 increased TEER by 11.4 Omega/cm(2) and reduced protein passage by 45.2%, whereas VEGF reduced TEER by 12.5 Omega/cm(2) but had no effect on protein passage. Both ang1 and VEGF modulate GEnC barrier properties, consistent with potential in vivo roles; ang1 stabilizing the endothelium and resisting angiogenesis while VEGF induces the high permeability to water, characteristic of the glomerular endothelium.
The relative risk of aortic aneurysm in patients with giant cell arteritis compared with the general population of the UK
Authors: Joanna C Robson, Amit Kiran, Joe Maskell, Andrew Hutchings, Nigel Arden, Bhaskar Dasgupta, William Hamilton, Akan Emin, David Culliford, Raashid A Luqmani
Journal: Annals of the Rheumatic Diseases (2013)

To evaluate the risk of aortic aneurysm in patients with giant cell arteritis (GCA) compared with age-, gender- and location-matched controls.A UK General Practice Research Database (GPRD) parallel cohort study of 6999 patients with GCA and 41 994 controls, matched on location, age and gender, was carried out. A competing risk model using aortic aneurysm as the primary outcome and non-aortic-aneurysm-related death as the competing risk was used to determine the relative risk (subhazard ratio) between non-GCA and GCA subjects, after adjustment for cardiovascular risk factors.Comparing the GCA cohort with the non-GCA cohort, the adjusted subhazard ratio (95% CI) for aortic aneurysm was 1.92 (1.52 to 2.41). Significant predictors of aortic aneurysm were being an ex-smoker (2.64 (2.03 to 3.43)) or a current smoker (3.37 (2.61 to 4.37)), previously taking antihypertensive drugs (1.57 (1.23 to 2.01)) and a history of diabetes (0.32 (0.19 to 0.56)) or cardiovascular disease (1.98 (1.50 to 2.63)). In a multivariate model of the GCA cohort, male gender (2.10 (1.38 to 3.19)), ex-smoker (2.20 (1.22 to 3.98)), current smoker (3.79 (2.20 to 6.53)), previous antihypertensive drugs (1.62 (1.00 to 2.61)) and diabetes (0.19 (0.05 to 0.77)) were significant predictors of aortic aneurysm.Patients with GCA have a twofold increased risk of aortic aneurysm, and this should be considered within the range of other risk factors including male gender, age and smoking. A separate screening programme is not indicated. The protective effect of diabetes in the development of aortic aneurysms in patients with GCA is also demonstrated.
Hepatic and Renal Toxicities Associated with Perchloroethylene
Authors: Lawrence H. Lash, Jean C. Parker
Journal: Pharmacological Reviews (2001)

Metabolism of perchloroethylene (Perc) occurs by cytochrome P450-dependent oxidation and glutathione (GSH) conjugation. The cytochrome P450 pathway generates tri- and dichloroacetate as metabolites of Perc, and these are associated with hepatic toxicity and carcinogenicity. The GSH conjugation pathway is associated with generation of reactive metabolites selectively in the kidneys and with Perc-induced renal toxicity and carcinogenicity. Physiologically based pharmacokinetic models have been developed for Perc in rodents and in humans. We propose the addition of a submodel that incorporates the GSH conjugation pathway and the kidneys as a target organ. Long-term bioassays of Perc exposure in laboratory animals have identified liver tumors in male and female mice, kidney tumors in male rats, and mononuclear cell leukemia in male and female rats. Increases in incidence of non-Hodgkin's lymphoma and of cervical, esophageal, and urinary bladder cancer have been observed for workers exposed to Perc. Limited, and not always consistent, evidence is available concerning the kidneys as a target organ for Perc in humans. Three potential modes of action for Perc-induced liver tumorigenesis are: 1) modification of signaling pathways; 2) cytotoxicity, cell death, and reparative hyperplasia; and 3) direct DNA damage. Four potential modes of action for Perc-induced renal tumorigenesis are: 1) peroxisome proliferation, 2) alpha-2u-globulin nephropathy, 3) genotoxicity leading to somatic mutation, and 4) acute cytotoxicity and necrosis leading to cell proliferation. Finally, the epidemiological and experimental data are assessed and use of toxicity information in the development of a reference dose and a reference concentration for human Perc exposure are presented.
Following the LINEs: An Analysis of Primate Genomic Variation at Human-Specific LINE-1 Insertion Sites
Authors: B. J. Vincent
Journal: Molecular Biology and Evolution (2003)

The L1 Ta subfamily of long interspersed elements (LINEs) consists exclusively of human-specific L1 elements. Polymerase chain reaction–based screening in nonhuman primate genomes of the orthologous sites for 249 human L1 Ta elements resulted in the recovery of various types of sequence variants for approximately 12% of these loci. Sequence analysis was employed to capture the nature of the observed variation and to determine the levels of gene conversion and insertion site homoplasy associated with LINE elements. Half of the orthologous loci differed from the predicted sizes due to localized sequence variants that occurred as a result of common mutational processes in ancestral sequences, often including regions containing simple sequence repeats. Additional sequence variation included genomic deletions that occurred upon L1 insertion, as well as successive mobile element insertions that accumulated within a single locus over evolutionary time. Parallel independent mobile element insertions at orthologous loci in distinct species may introduce homoplasy into retroelement-based phylogenetic and population genetic data. We estimate the overall frequency of parallel independent insertion events at L1 insertion sites in seven different primate species to be very low (0.52%). In addition, no cases of insertion site homoplasy involved the integration of a second L1 element at any of the loci, but rather largely involved secondary insertions of Alu elements. No independent mobile element insertion events were found at orthologous loci in the human and chimpanzee genomes. Therefore, L1 insertion polymorphisms appear to be essentially homoplasy free characters well suited for the study of population genetics and phylogenetic relationships within closely related species.
Is the P300 component a manifestation of context updating?
Authors: Emanuel Donchin, Michael G. H. Coles
Journal: Behavioral and Brain Sciences (1988)

To understand the endogenous components of the event-related brain potential (ERP), we must use data about the components' antecedent conditions to form hypotheses about the information-processing function of the underlying brain activity. These hypotheses, in turn, generate testable predictions about the consequences of the component. We review the application of this approach to the analysis of the P300 component. The amplitude of the P300 is controlled multiplicatively by the subjective probability and the task relevance of the eliciting events, whereas its latency depends on the duration of stimulus evaluation. These and other factors suggest that the P300 is a manifestation of activity occurring whenever one's model of the environment must be revised. Tests of three predictions based on this "context updating" model are reviewed. Verleger's critique is based on a misconstrual of the model as well as a partial and misleading reading of the relevant literature.
Development and validation of a rapid, generic measure of disease control from the patient's perspective: the IBD-Control questionnaire
Authors: Keith Bodger, Clare Ormerod, Daniela Shackcloth, Melanie Harrison
Journal: Gut (2013)

The use of patient reported outcome measures to support routine inflammatory bowel disease (IBD) care is not widespread and suggests that existing questionnaires lack relevance to day-to-day decisions or are too cumbersome to administer. We developed a simple, generic tool for capturing disease control from the patient's perspective to address these barriers.Development based on literature review, patient focus groups/interviews and a steering group, defining a limited set of generic questions. The 'IBD-Control' questionnaire comprises 13 items plus a visual analogue scale (VAS) (0-100). Prospective validation involved baseline completion of IBD-Control, quality of life (QoL) questionnaire (UK-IBD-Q), EuroQol (EQ-5D), Hospital Anxiety and Depression Score; and clinician assessment (blinded to questionnaire; recording Harvey-Bradshaw Index or Simple Clinical Colitis Activity Index; Global Clinician Rating; treatment outcome).299 patients returned baseline surveys (Crohn's disease, n=160; ulcerative colitis, n=139) and 138 attended for repeat visits. Completion time (mean; SD): 1 min 15 s; 25 s; Internal consistency: Cronbach's α for all 13 items (0.85); for subgroup of eight questions ('IBD-Control-8'; 0.86). Strong correlation between IBD-Control-8 and IBD-Control-VAS (r=0.81). Test-retest reliability (2 week repeat): intra-class correlation=0.97 for IBD-Control-8 and 0.96 for IBD-Control-VAS. Construct validity: Moderate-to-strong correlations between IBD-Control-8 and IBD-Control-VAS versus activity indices, UK-IBD-Q and EQ-5D (utility) with r values 0.52-0.86. Discriminant validity (mean instrument scores for remission, mild, moderate or severe): p<0.001 (analysis of variance (ANOVA)). Sensitivity to change: Effect sizes: 0.76-1.44.The IBD-Control is a rapid, reliable, valid and sensitive instrument for measuring overall disease control from the patient's perspective. Unlike existing patient reported outcome measures, its simplicity, ease-of-use and generic applicability make it a candidate for supporting routine care.
Cytoplasmic CD24 Expression in Colorectal Cancer Independently Correlates with Shortened Patient Survival
Authors: Wilko Weichert, Carsten Denkert, Mick Burkhardt, Tserenchunt Gansukh, Joachim Bellach, Peter Altevogt, Manfred Dietel, Glen Kristiansen
Journal: Clinical Cancer Research (2005)

Abstract Purpose: CD24 is a cell adhesion molecule that has been implicated in metastatic tumor progression of various solid tumors. We aimed to clarify the expression patterns of CD24 in colorectal cancer and to correlate these to clinicopathologic variables including patient survival. Experimental Design: 147 colorectal carcinomas and two colon carcinoma cell lines were immunostained for CD24. Cytoplasmic and membranous immunoreactivity were semiquantitatively scored. Fisher's exact test, χ2 test for trends, Kaplan-Meier analysis, and Cox's regression were applied. Results: The cell line CX-2 showed only a minimal membranous CD24 immunoreactivity, in contrast to HT29, which stained strongly in the cytoplasm. In colorectal cancer, 68.7% of the tumors showed membranous CD24 staining, whereas 84.4% showed cytoplasmic staining. In 10% of cases, an exceptionally strong cytoplasmic CD24 expression was observed. The latter significantly correlated to higher tumor stages (Dukes and pT), nodal or systemic metastasis, and higher tumor grade. In survival analysis, strong cytoplasmic CD24 expression correlated significantly (Cox's regression: P = 0.012, relative risk = 3.7) to shortened patient survival in the group of cases without distant metastases. Conclusions: CD24 is commonly up-regulated in colorectal cancer and is a new independent prognostic marker which corroborates the importance of CD24 in tumor progression of this disease.
Distribution of dyspnea etiologies among patients with either acute or chronic breathlessness and normal cardiorespiratory function
Authors: Stylianos Michaelides, George Bablekos, Eftychia Kourtelessi, Alexandros Alexopoulos, George Ionas, Konstantinos Paraskevopoulos, Sofia Karagianni
Journal: European Respiratory Journal (2012)

We aimed at investigating the distribution of dyspnea etiology in patients with normal cardiorespiratory function (NCF). We studied 57 pts. (33 male & 24 female) aged 58.4±7.8 yrs. who presented at the Outpatients9 Department during the past 12 months, complaining of breathlessness with no other respiratory symptoms. Patients compalained of either acute breathlessness (AB group- starting within the past 48 hrs.) or chronic (CB-group-more than 48 hrs. duration). All had a chest X-ray along with spirometry, arterial blood gases and heart ultrasound, having been rated as normal.Those in whom diagnosis was not primarily established, underent further testing including hormonal profile, lung perfusion scan, computerized chest tomography & angiography and respiratory muscle testing. In AB group (31 pts: 15 male & 19 female) aged 46.4±4.7 yrs. the final diagnosis was: 18 pts. (58%) acute psychogenic hyperventilation syndrome (HS), 11 (36%) anemia due to silent gastrointenstinal bleeding (GB) and 2 (6%) hyperthyroidism (HT). In CB group (26 pts:18 male & 8 female) aged 61.3±6.8 yrs. the final diagnosis was: 6 pts. (23%) HS, 7 (27%) GB, 3 (12%) obesity-deconditioning (OD, 3 (12%) anemia of renal failure syndrome (RF), 2 (8%), HT 2 (8%), diaphragmatric weakness (DW), 2 (8%) chronic thromboembolic pulmonary disease (TD) and 1 (2%) had brain tumor (BT). Our results indicate that patients with NCFAB was most frequently due to either HS or GB while those with CB these diagnoses were less frequent. HS was more frequent in females while GB in males. Even with NCF, a minority of CB patients had DW or or TD which without specific testing might have been missed.
Loss of cerebrovascular autoregulation in experimental meningitis in rabbits.
Authors: J H Tureen, R J Dworkin, S L Kennedy, M Sachdeva, M A Sande
Journal: Journal of Clinical Investigation (1990)

The present study was designed to determine whether cerebrovascular autoregulation is intact in experimental meningitis and to examine the relationship between fluctuations in cerebral blood flow (CBF) and increased intracranial pressure (ICP). Measurements of CBF were determined by the radionuclide microsphere technique in rabbits with experimental Streptococcus pneumoniae meningitis with simultaneous ICP monitoring via an implanted epidural catheter. CBF and ICP measurements were determined at baseline and when mean arterial blood pressure (MABP) was artificially manipulated by either pharmacologic or mechanical means. CBF was pressure passive with MABP through a range of 30-120 torr, and ICP directly correlated with CBF. These findings indicate that autoregulation of the cerebral circulation is lost during bacterial meningitis, resulting in a critical dependency of cerebral perfusion on systemic blood pressure, and that the parallel changes in ICP and in CBF suggest that fluctuations in CBF may influence intracranial hypertension in this disease.