tbuckley/cabot-search huggingface dataset:
MicroRNA-29a regulates intestinal membrane permeability in patients with irritable bowel syndrome
Authors: Q. Zhou, W. W. Souba, C. M. Croce, G. N. Verne
Journal: Gut (2009)

<h3>Background</h3> The molecular mechanisms underlying the pathophysiology of irritable bowel syndrome (IBS) are poorly understood. One mechanism may involve increased intestinal permeability that is reversed with glutamine supplementation. Our goal was to evaluate the expression of glutamine synthetase and its complementary miRNA in blood microvesicles and gut tissues of IBS patients with increased intestinal membrane permeability. <h3>Methods</h3> We evaluated 19 diarrhoea-predominant IBS patients and 10 controls for intestinal membrane permeability using the lactulose/mannitol method. miRNA expression was evaluated in blood microvesicles and gut tissue. To further confirm the relationship between miRNA and glutamine synthetase expression, cell culture experiments were conducted. Glutamine synthetase was also evaluated in the gut tissues of patients. <h3>Results</h3> A subset of patients with IBS (8/19, 42%) had increased intestinal membrane permeability and decreased glutamine synthetase expression compared to patients with IBS normal membrane permeability, and to controls. Expression of miR-29a was increased in blood microvesicles, small bowel and colon tissues of IBS patients with increased intestinal membrane permeability. Increased intestinal permeability was modulated by miR-29a which has a complementary site in the 3′-UTR of the GLUL gene. <h3>Conclusions</h3> The results support the conclusion that GLUL regulates intestinal membrane permeability and miR-29a regulates both GLUL and intestinal membrane permeability. The data suggests that miR-29a effects on intestinal membrane permeability may be due to its regulation of GLUL. Targeting this signalling pathway could lead to a new therapeutic approach to the treatment of patients with IBS, especially because small molecules that mimic or inhibit miRNA-based mechanisms are readily available.
Differential Effects of Notch Ligands Delta-1 and Jagged-1 in Human Lymphoid Differentiation
Authors: Ana C. Jaleco, Hélia Neves, Erik Hooijberg, Paula Gameiro, Nuno Clode, Matthias Haury, Domingos Henrique, Leonor Parreira
Journal: The Journal of Experimental Medicine (2001)

Notch signaling is known to differentially affect the development of lymphoid B and T cell lineages, but it remains unclear whether such effects are specifically dependent on distinct Notch ligands. Using a cell coculture assay we observed that the Notch ligand Delta-1 completely inhibits the differentiation of human hematopoietic progenitors into the B cell lineage while promoting the emergence of cells with a phenotype of T cell/natural killer (NK) precursors. In contrast, Jagged-1 did not disturb either B or T cell/NK development. Furthermore, cells cultured in the presence of either Delta-1 or Jagged-1 can acquire a phenotype of NK cells, and Delta-1, but not Jagged-1, permits the emergence of a de novo cell population coexpressing CD4 and CD8. Our results thus indicate that distinct Notch ligands can mediate differential effects of Notch signaling and provide a useful system to further address cell-fate decision processes in lymphopoiesis.
Histone Deacetylase Inhibitors Synergize p300 Autoacetylation that Regulates Its Transactivation Activity and Complex Formation
Authors: Daniel P. Stiehl, Donna M. Fath, Dongming Liang, Yubao Jiang, Nianli Sang
Journal: Cancer Research (2007)

Abstract p300/cyclic AMP–responsive element binding protein–binding protein (CBP) are general coactivators for multiple transcription factors involved in various cellular processes. Several highly conserved domains of p300/CBP serve as interacting sites for transcription factors and regulatory proteins. Particularly, the intrinsic histone acetyltransferase (HAT) activity and transactivation domains (TAD) play essential roles for their coactivating function. Autoacetylation of p300/CBP is commonly observed in cell-free HAT assays and has been implicated in the regulation of their HAT activity. Here, we show that six lysine-rich regions in several highly conserved functional domains of p300 are targeted by p300HAT for acetylation in cell-free systems. We show that p300 is susceptible to acetylation in cultured tumor cells and that its acetylation status is affected by histone deacetylase inhibitor trichostatin A. We further show that either treatment with deacetylase inhibitors or coexpression of Gal4-p300HAT, which alone has no transactivation activity, stimulates the activity of the COOH-terminal TAD of p300 (p300C-TAD). We have defined the minimal p300C-TAD and show that it is sufficient to respond to deacetylase inhibitors and is a substrate for p300HAT. Finally, we show that acetylated p300 possesses enhanced ability to interact with p53. Taken together, our data suggest that acetylation regulates p300C-TAD and that acetylation of p300/CBP may contribute to the dynamic regulation of their complex formation with various interacting partners. [Cancer Res 2007;67(5):2256–64]
Thromboxane B2 in cardiac lymph. Effect of superoxide dismutase and catalase during myocardial ischemia and reperfusion.
Authors: L H Michael, Z Zhang, C J Hartley, R Bolli, A A Taylor, M L Entman
Journal: Circulation Research (1990)

Neutrophils have been implicated in the genesis of myocardial ischemia-reperfusion injury, and their mechanism of action has been linked to the production of reactive oxygen species, fatty acid-derived prostanoids, and leukotrienes. In this study, we examined the potential relation between production of reactive oxygen species and cyclooxygenase-derived autacoids by studying the effects of superoxide dismutase (SOD) and catalase (CAT) on the rise in thromboxane formation observed with myocardial ischemia and reperfusion. Immunoreactive thromboxane B2 was measured in cardiac lymph from conscious dogs during reperfusion after a 60-minute occlusion in the presence of infusions of SOD alone, CAT alone, and a combination of SOD and CAT. Reperfusion after 60 minutes of ischemia causes an immediate elevation in thromboxane B2. SOD and CAT infusion prevented this rise in thromboxane B2 as did infusion of SOD alone. The ability of SOD-CAT to suppress thromboxane B2 production dissipated within 3 hours after the cessation of infusion, at which time thromboxane B2 excretion increased. The modulation of fatty acid oxygenases by reactive oxygen species may be a very important pathogenic factor in considering the origin of the protective effect of antioxidants in the setting of myocardial ischemia-reperfusion injury.
The Breast Cancer Alternative Hypothesis: Is There Evidence to Justify Replacing It?
Authors: Bernard Fisher, Stewart J. Anderson
Journal: Journal of Clinical Oncology (2009)

SUMMARY Inconclusion: ● During the last two decades, as a result of the use of systemictherapy in conjunction with breast-conservation surgery andradiation therapy, the incidence of locoregional recurrencehas been reduced to a level where further reduction, a goalworthyofachieving,islikelytohavelittleimpactonsurvival. ● Despitetheextensiveinformationpresentedinthiscommen-tary, there is no new scientiﬁcally based evidence to justifyreplacing the current breast cancer hypothesis. ● It is likely that ﬁndings from research related to molecularbiologyandgeneticswillbethesourceofinformationthatwillresult in a new, testable thesis that will eventually replace thealternative hypothesis and thus the paradigm that currentlygoverns the treatment of breast cancer. Status of the Breast Cancer Hypothesis www.jco.org © 2009 by American Society of Clinical Oncology 373 Downloaded from jco.ascopubs.org on June 6, 2013. For personal use only. No other uses without permission.Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
Potent Twice-Weekly Rifapentine-containing Regimens in Murine Tuberculosis
Authors: Ian M. Rosenthal, Kathy Williams, Sandeep Tyagi, Charles A. Peloquin, Andrew A. Vernon, William R. Bishai, Jacques H. Grosset, Eric L. Nuermberger
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Recent studies have demonstrated that intermittent administration of rifamycin-based regimens results in higher rates of tuberculosis relapse and treatment failure compared with daily therapy. Twice-weekly treatment with rifampin, isoniazid, and pyrazinamide may be improved by increasing Mycobacterium tuberculosis exposure to rifamycin by substituting rifapentine for rifampin.To test this hypothesis, we compared the activities of standard daily and twice-weekly rifampin plus isoniazid-based regimens to those of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing regimens in the murine model of tuberculosis. Relapse rates were assessed after 4, 5, and 6 mo of treatment to assess stable cure. Single- and multiple-dose pharmacokinetics of rifampin and rifapentine were also determined.After 2 mo of treatment, twice-weekly therapy with rifapentine (15 or 20 mg/kg), moxifloxacin, and pyrazinamide was significantly more active than standard daily or twice-weekly therapy with rifampin, isoniazid, and pyrazinamide. Stable cure was achieved after 4 mo of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing therapy, but only after 6 mo of standard daily therapy. Twice-weekly rifapentine (15 mg/kg) displayed more favorable pharmacodynamics than did daily rifampin (10 mg/kg).By virtue of the enhanced rifamycin exposure, twice-weekly regimens containing rifapentine (15 or 20 mg/kg) may permit shortening the current treatment duration by 2 mo. Such regimens warrant clinical investigation.
Prognostic and Predictive Roles of High-Degree Microsatellite Instability in Colon Cancer: A National Cancer Institute–National Surgical Adjuvant Breast and Bowel Project Collaborative Study
Authors: George P. Kim, Linda H. Colangelo, H. Samuel Wieand, Soonmyung Paik, Ilan R. Kirsch, Norman Wolmark, Carmen J. Allegra
Journal: Journal of Clinical Oncology (2007)

The role of high-degree microsatellite instability (MSI-H) as a marker to predict benefit from adjuvant chemotherapy remains unclear.To help define its impact, we conducted an analysis of National Surgical Adjuvant Breast and Bowel Project (NSABP) patients who were randomly assigned to a surgery-alone group (untreated cohort) and patients assigned to an adjuvant fluorouracil (FU) -treated group (treated cohort). MSI-H and other potential markers were assessed (TGF-BRII, p53, thymidylate synthase, and Ki67).In all, 98 (18.1%) of 542 patients exhibited MSI-H, and there was a strong inverse relationship between MSI-H and mutant p53 status (P < .001). The prognostic analyses showed increased recurrence-free survival (RFS) for MSI-H patients versus MSS/MSI-L patients (P = .10), but showed no difference in overall survival (OS; P = .67). There was a potential interaction between MSI-H and mutant p53 in terms of improved RFS (P = .03). In the predictive marker analysis, we observed no interaction between MSI status and treatment for either RFS (P = .68) or OS (P = .62). Hazard ratios (HR) for RFS for MSI-H versus MSS/MSI-L patients were 0.77 (95% CI, 0.40 to 1.48) in the untreated-patients group and 0.60 (95% CI, 0.30 to 1.19) in the treated-patients group. HRs for OS were 0.82 (95% CI, 0.44 to 1.51) and 1.02 (95% CI, 0.56 to 1.85) for the respective groups. There was a trend toward improved RFS in patients with MSI-H and mutant p53.These results do not support the use of MSI-H as a predictive marker of chemotherapy benefit.
Training and supervision of obstetric senior house officers.
Authors: M Ennis
Journal: BMJ (1991)

The differences observed in neuropsychological test results might represent a trait characteristic of a particular group of patients who have frequent hypo- glycaemia without having received intensified insulin treatment.The authors were also well aware of this possibility.5Diabetic patients with near normoglycaemia differ from people without diabetes with regard to substrate utilisation in the brain and regional cerebral blood flow during normoglycaemia.33These diabetic patients did not, however, differ from their non-diabetic counter- parts in neuropsychological function.33The differences observed in blood flow and substrate utilisation are therefore probably not related to any anatomical defects of clinical significance.Intensified conventional insulin treatment, which retarded the development of microvascular diabetic complications, led to an increased frequency of serious hypoglycaemic episodes, during which patients needed help from someone else and which more often resulted in hypoglycaemic coma.Although these episodes were upsetting for patients and poten- tially dangerous-for example, if they occurred when driving a car-they did not cause permanent cognitive deficit.
Managing neutropenic sepsis
Authors: S M. Crawford
Journal: BMJ (2009)

The fever of flu may mimic neutropenic fever. Therefore a policy for managing fever during the A/H1N1 flu pandemic in patients with cancer who are receiving chemotherapy has been developed with detailed advice from Professor Nick Phin and Dr Hongxin Zhao of the Health Protection Agency.

Patients receiving chemotherapy who develop a fever should telephone the emergency …
Platelet-activating factor dilates efferent arterioles through glomerulus-derived nitric oxide.
Authors: S Arima, Y Ren, L A Juncos, S Ito
Journal: Journal of the American Society of Nephrology (1996)

Despite evidence that platelet-activating factor (PAF) is produced by the glomerulus, its direct action on the glomerular microcirculation is poorly understood. It was recently reported that at picomolar concentrations, PAF dilates isolated microperfused afferent arterioles (Af-Art) via nitric oxide (NO). The present study tested the hypothesis that PAF acts on the glomerulus to release NO, which in turn controls the resistance of the efferent arteriole (Ef-Art). Rabbit Ef-Art were perfused from the distal end (retrograde perfusion [RP]) to eliminate the influence of the glomerulus, or through the glomerulus from the end of the Af-Art (orthograde perfusion [OP]) to maintain the influence of the glomerulus. Ef-Art were preconstricted by approximately 40% with norepinephrine and increasing doses of PAF were added to both the arteriolar perfusate and bath. Only with OP did PAF at picomolar concentrations cause significant dilation: at 400 pmol, the diameter increased by 64 +/- 11% from the preconstricted level (N = 6, P < 0.01). This dilation was completely abolished by pretreatment with an NO-synthesis inhibitor. To study its possible constrictor action, PAF was added to nonpreconstricted Ef-Art. At nanomolar concentrations, PAF constricted Ef-Art similarly in both RP and OP: at 40 nM, the diameter decreased by 24 +/- 4% (N = 6, P < 0.01) and 20 +/- 2% (N = 6, P < 0.01), respectively. This constriction was attenuated by pretreatment with indomethacin (Indo) in both RP (14 +/- 2%, N = 7; P < 0.02 versus without Indo) and OP (10 +/- 2%, N = 6; P < 0.02 versus without Indo). In conclusion: (1) at picomolar concentrations, PAF stimulates the glomerulus to release NO, which in turn dilates the Ef-Art; and (2) at nanomolar concentrations, PAF constricts the Ef-Art partly through release of cyclooxygenase metabolites. Thus, PAF may play a role in glomerular hemodynamics under various physiological and pathological conditions.
Influence of Continuous Physiologic Hyperinsulinemia on Glucose Kinetics and Counterregulatory Hormones in Normal and Diabetic Humans
Authors: Luigi Saccà, Robert Sherwin, Rosa Hendler, Philip Felig
Journal: Journal of Clinical Investigation (1979)

The effects of continuous infusions of insulin in physiologic doses on glucose kinetics and circulating counterregulatory hormones (epinephrine, norepinephrine, glucagon, cortisol, and growth hormone) were determined in normal subjects and diabetics. The normals received insulin at two dose levels (0.4 and 0.25 mU/kg per min) and the diabetics received the higher dose (0.4 mU/kg per min) only.
Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics
Authors: Patrick Flood-Page, Andrew Menzies-Gow, Simon Phipps, Sun Ying, Arun Wangoo, Mara S. Ludwig, Neil Barnes, Douglas Robinson, A. Barry Kay
Journal: Journal of Clinical Investigation (2003)

Eosinophil-derived TGF-β has been implicated in remodeling events in asthma. We hypothesized that reduction of bronchial mucosal eosinophils with anti–IL-5 would reduce markers of airway remodeling. Bronchial biopsies were obtained before and after three infusions of a humanized, anti–IL-5 monoclonal antibody (mepolizumab) in 24 atopic asthmatics in a randomized, double-blind, placebo-controlled study. The thickness and density of tenascin, lumican, and procollagen III in the reticular basement membrane (RBM) were quantified immunohistochemically by confocal microscopy. Expression of TGF-β1 mRNA by airway eosinophils was assessed by in situ hybridization, and TGF-β1 protein was measured in bronchoalveolar lavage (BAL) fluid by ELISA. At baseline, airway eosinophil infiltration and ECM protein deposition was increased in the RBM of asthmatics compared with nonasthmatic controls. Treating asthmatics with anti–IL-5 antibody, which specifically decreased airway eosinophil numbers, significantly reduced the expression of tenascin, lumican, and procollagen III in the bronchial mucosal RBM when compared with placebo. In addition, anti–IL-5 treatment was associated with a significant reduction in the numbers and percentage of airway eosinophils expressing mRNA for TGF-β1 and the concentration of TGF-β1 in BAL fluid. Therefore eosinophils may contribute to tissue remodeling processes in asthma by regulating the deposition of ECM proteins.
Lymphocyte specificity to protein antigens. II. Fine specificity of T-cell activation with cytochrome c and derived peptides as antigenic probes.
Authors: G Corradin, J M Chiller
Journal: The Journal of Experimental Medicine (1979)

Murine T-lymphocyte specificity was determined in a system of antigen driven in vitro T-cell proliferation using cytochrome c molecules from different species, their derived peptides and reconstituted hybrid proteins. It was observed that primed T cells could discriminate between peptide fragments which differed from each other at a single amino acid residue. These conclusions were substantiated by the pattern of cross-reactivity noted in the response of closely related cytochrome c proteins as well as when artificial hybrid molecules reconstituted by the covalent linkage of peptide fragments were analyzed. The pattern of specificity observed appeared to be haplotype (BDF1) dependent although similar conclusions about the fine specificity of T cells in the response to cytochrome c have been obtained in other strains but associated with different residues.
Translating the Therapeutic Potential of AZD4547 in <i>FGFR1</i>-Amplified Non–Small Cell Lung Cancer through the Use of Patient-Derived Tumor Xenograft Models
Authors: Jingchuan Zhang, Lin Zhang, Xinying Su, Ming Li, Liang Xie, Florian Malchers, ShuQiong Fan, XiaoLu Yin, YanPing Xu, Kunji Liu, Zhengwei Dong, Guanshan Zhu, Ziliang Qian, Lili Tang, Ping Zhan, Qunsheng Ji, Elaine Kilgour, Paul D. Smith, A. Nigel Brooks, Roman K. Thomas, Paul R. Gavine
Journal: Clinical Cancer Research (2012)

Abstract Purpose: To investigate the incidence of FGFR1 amplification in Chinese non–small cell lung cancer (NSCLC) and to preclinically test the hypothesis that the novel, potent, and selective fibroblast growth factor receptor (FGFR) small-molecule inhibitor AZD4547 will deliver potent antitumor activity in NSCLC FGFR1–amplified patient-derived tumor xenograft (PDTX) models. Experimental Design: A range of assays was used to assess the translational relevance of FGFR1 amplification and AZD4547 treatment including in vitro lung cell line panel screening and pharmacodynamic (PD) analysis, FGFR1 FISH tissue microarray (TMA) analysis of Chinese NSCLC (n = 127), and, importantly, antitumor efficacy testing and PD analysis of lung PDTX models using AZD4547. Results: The incidence of FGFR1 amplification within Chinese patient NSCLC tumors was 12.5% of squamous origin (6 of 48) and 7% of adenocarcinoma (5 of 76). AZD4547 displayed a highly selective profile across a lung cell line panel, potently inhibiting cell growth only in those lines harboring amplified FGFR1 (GI50 = 0.003–0.111 μmol/L). AZD4547 induced potent tumor stasis or regressive effects in four of five FGFR1-amplified squamous NSCLC PDTX models. Pharmacodynamic modulation was observed in vivo, and antitumor efficacy correlated well with FGFR1 FISH score and protein expression level. Conclusions: This study provides novel epidemiologic data through identification of FGFR1 gene amplification in Chinese NSCLC specimens (particularly squamous) and, importantly, extends the clinical significance of this finding by using multiple FGFR1-amplified squamous lung cancer PDTX models to show tumor stasis or regression effects using a specific FGFR inhibitor (AZD4547). Thus, the translational science presented here provides a strong rationale for investigation of AZD4547 as a therapeutic option for patients with squamous NSCLC tumors harboring amplification of FGFR1. Clin Cancer Res; 18(24); 6658–67. ©2012 AACR.
Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families
Authors: Nadia Akawi, Jeremy McRae, Morad Ansari, Meena Balasubramanian, Moira Blyth, Angela F Brady, Stephen Clayton, Trevor Cole, Charu Deshpande, Tomas W Fitzgerald, Nicola Foulds, Richard Francis, George Gabriel, Sebastian S Gerety, Judith Goodship, Emma Hobson, Wendy D Jones, Shelagh Joss, Daniel King, Nikolai Klena, Ajith Kumar, Melissa Lees, Chris Lelliott, Jenny Lord, Dominic McMullan, Mary O'Regan, Deborah Osio, Virginia Piombo, Elena Prigmore, Diana Rajan, Elisabeth Rosser, Alejandro Sifrim, Audrey Smith, Ganesh J Swaminathan, Peter Turnpenny, James Whitworth, Caroline F Wright, Helen V Firth, Jeffrey C Barrett, Cecilia W Lo, David R FitzPatrick, Matthew E Hurles
Journal: Nature Genetics (2015)
Nottingham knee osteoarthritis risk prediction models
Authors: W. Zhang, D. F. McWilliams, S. L. Ingham, S. A. Doherty, S. Muthuri, K. R. Muir, M. Doherty
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objectives</h3> (1) To develop risk prediction models for knee osteoarthritis (OA) and (2) to estimate the risk reduction that results from modification of potential risk factors. <h3>Method</h3> This was a 12-year retrospective cohort study undertaken in the general population in Nottingham, UK. Baseline risk factors were collected by questionnaire. Incident radiographic knee OA was defined by Kellgren and Lawrence (KL) score ≥2. Incident symptomatic knee OA was defined by KL ≥2 plus knee pain. Progression of knee OA was defined by KL ≥1 grade increase from baseline. A logistic regression model was used for prediction. Calibration and discrimination of the models were tested in the Osteoarthritis Initiative (OAI) population and Genetics of Osteoarthritis and Lifestyle (GOAL) population. ORs of the models were compared with those obtained from meta-analysis of existing literature. <h3>Results</h3> From a community sample of 424 people aged over 40, 3 risk prediction models were developed. These included incidence of radiographic knee OA, incidence of symptomatic knee OA and progression of knee OA. All models had good calibration and moderate discrimination power in OAI and GOAL. The ORs lied within the 95% CIs of the published studies. The risk reduction due to modifying obesity at the individual and the population levels were demonstrated. <h3>Conclusions</h3> Risk prediction of knee OA based on the well established, common modifiable risk factors has been established. The models may be used to predict the risk of knee OA, and risk reduction due to preventing a specific risk factor.