tbuckley/cabot-search huggingface dataset:
Role of the ATP-Binding Cassette Transporter <i>Abcg2</i> in the Phenotype and Function of Cardiac Side Population Cells
Authors: Otmar Pfister, Angelos Oikonomopoulos, Konstantina-Ioanna Sereti, Regina L. Sohn, Darragh Cullen, Gabriel C. Fine, Frédéric Mouquet, Karen Westerman, Ronglih Liao
Journal: Circulation Research (2008)

Recently, the side population (SP) phenotype has been introduced as a reliable marker to identify subpopulations of cells with stem/progenitor cell properties in various tissues. We and others have identified SP cells from postmitotic tissues, including adult myocardium, in which they have been suggested to contribute to cellular regeneration following injury. SP cells are identified and characterized by a unique efflux of Hoechst 33342 dye. Abcg2 belongs to the ATP-binding cassette (ABC) transporter superfamily and constitutes the molecular basis for the dye efflux, hence the SP phenotype, in hematopoietic stem cells. Although Abcg2 is also expressed in cardiac SP (cSP) cells, its role in regulating the SP phenotype and function of cSP cells is unknown. Herein, we demonstrate that regulation of the SP phenotype in cSP cells occurs in a dynamic, age-dependent fashion, with Abcg2 as the molecular determinant of the cSP phenotype in the neonatal heart and another ABC transporter, Mdr1, as the main contributor to the SP phenotype in the adult heart. Using loss- and gain-of-function experiments, we find that Abcg2 tightly regulates cell fate and function. Adult cSP cells isolated from mice with genetic ablation of Abcg2 exhibit blunted proliferation capacity and augmented cell death. Conversely, overexpression of Abcg2 is sufficient to enhance cell proliferation, although with a limitation of cardiomyogenic differentiation. In summary, for the first time, we reveal a functional role for Abcg2 in modulating the proliferation, differentiation, and survival of adult cSP cells that goes beyond its distinct role in Hoechst dye efflux.
Inhibition of cell growth in human glioblastoma cell lines by farnesyltransferase inhibitor SCH66336
Authors: Tricia L. Glass, Ta-Jen Liu, W.K. Alfred Yung
Journal: Neuro-Oncology (2000)

Ras activation occurs through stimulation of an upstream growth factor receptor such as epidermal growth factor receptor (EGFR). The ultimate effect of Ras is to induce nuclear transcription via a signaling pathway sequentially involving Raf, MAP kinase kinase (MEK), and mitogen-activated protein kinase (MAPK). To transform cells, Ras oncoproteins must be posttranslationally modified with a farnesyl group in a reaction catalyzed by farnesyl protein transferase. Farnesyltransferase inhibitors, therefore, have been proposed as potent anticancer agents. This study demonstrates the growth-inhibitory effects of farnesyltransferase inhibitor SCH66336 on human glioblastoma cell lines U-251 MG, U-251/E4 MG (a stably transfected cell line with elevated EGFR expression), and U-87 MG. As determined by (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl)-2H-tetraz olium, inner salt) (MTS) and viability assays, the concentration required to achieve 50% inhibition (IC50) ranged from 30 μM (single 24-h treatment) to 10 μM (5-day treatment). U-251/E4 MG with overexpression of EGFR were more sensitive than U-251 MG parental cells. These observations were also supported by soft agar analysis. Cells treated with SCH66336 underwent G2 arrest. Western blot analysis revealed a decrease in phospho-MAPK levels upon treatment with 10 μM SCH66336, whereas MAPK levels were unaffected by the drug. Interestingly, increased expression of EGFR was observed in U-251 MG and U-251/E4 MG but not in U-87 MG in the presence of the inhibitor. These results demonstrate that SCH66336 inhibits viability and anchorage-independent growth in a time- and dose-dependent manner in glioblastoma cell lines U-251 MG, U-251/E4 MG, and U-87 MG via a signal transduction pathway involving the down-regulation of phospho-MAPK. Overexpression of EGFR appears to alter cellular sensitivity to farnesyltransferase inhibitors. This may have a particularly important implication in glioblastoma, where over 50% of tumors have amplification and overexpression of EGFR.
CYTOCHROME P450 UBIQUITINATION: Branding for the Proteolytic Slaughter?
Authors: Maria Almira Correia, Sheila Sadeghi, Eduardo Mundo-Paredes
Journal: The Annual Review of Pharmacology and Toxicology (2004)

▪ Abstract The hepatic cytochromes P450 (P450s) are monotopic endoplasmic reticulum (ER)-anchored hemoproteins engaged in the enzymatic oxidation of a wide variety of endo- and xenobiotics. In the course of these reactions, the enzymes generate reactive O 2 species and/or reactive metabolic products that can attack the P450 heme and/or protein moiety and structurally and functionally damage the enzyme. The in vivo conformational unraveling of such a structurally damaged P450 signals its rapid removal via the cellular sanitation system responsible for the proteolytic disposal of structurally aberrant, abnormal, and/or otherwise malformed proteins. A key player in this process is the ubiquitin (Ub)-dependent 26S proteasome system. Accordingly, the structurally deformed P450 protein is first branded for recognition and proteolytic removal by the 26S proteasome with an enzymatically incorporated polyUb tag. P450s of the 3A subfamily such as the major human liver enzyme CYP3A4 are notorious targets for this process, and they represent excellent prototypes for the understanding of integral ER protein ubiquitination. Not all the participants in hepatic CYP3A ubiquitination and subsequent proteolytic degradation have been identified. The following discussion thus addresses the various known and plausible events and/or cellular participants involved in this multienzymatic P450 ubiquitination cascade, on the basis of our current knowledge of other eukaryotic models. In addition, because the detection of ubiquitinated P450s is technically challenging, the critical importance of appropriate methodology is also discussed.
Relationship between tracheotomy and ventilator-associated pneumonia: a case control study
Authors: S. Nseir, C. Di Pompeo, E. Jozefowicz, B. Cavestri, H. Brisson, M. Nyunga, S. Soubrier, A. Durocher
Journal: European Respiratory Journal (2006)

The aim of the present study was to determine the relationship between tracheotomy and ventilator-associated pneumonia (VAP). The study used a retrospective case–control study design based on prospective data. All nontrauma immunocompetent patients, intubated and ventilated for &gt;7 days, were eligible for inclusion in the study. A diagnosis of VAP was based on clinical, radiographical and microbiological criteria. Four matching criteria were used, including duration of mechanical ventilation (MV). The indication and timing of tracheotomy were at the discretion of attending physicians. Univariate and multivariate analyses were performed to determine risk factors for VAP in cases (patients with tracheotomy) and controls (patients without tracheotomy). In total, 1,402 patients were eligible for inclusion. Surgical tracheotomy was performed in 226 (16%) patients and matching was successful for 177 (78%). The rate of VAP (22 versus 14 VAP episodes·1,000 MV-days −1 ) was significantly higher in controls than in cases. The rate of VAP after tracheotomy in cases, or after the corresponding day of MV in controls, was also significantly higher in control than in case patients (9.2 versus 4.8 VAP episodes·1,000 MV-days −1 ). In multivariate analysis, neurological failure (odds ratio (95% confidence interval) 2.7 (1.3–5)), antibiotic treatment (2.1 (1.1–3.2)) and tracheotomy (0.18 (0.1–0.3)) were associated with VAP. In summary, the present study demonstrates that tracheotomy is independently associated with decreased risk for ventilator-associated pneumonia.
Association of Physical Activity and Body Mass Index With Novel and Traditional Cardiovascular Biomarkers in Women
Authors: Samia Mora, I-Min Lee, Julie E. Buring, Paul M Ridker
Journal: JAMA (2006)

There are few data directly comparing the effects of physical activity and body weight on cardiovascular biomarkers.To examine the association of physical activity and body mass index (BMI, defined as weight in kilograms divided by the square of height in meters) alone and in combination with cardiovascular biomarkers.Cross-sectional analysis of 27,158 apparently healthy US women (mean age, 54.7 years) at the time of enrollment (1992-1995) in the Women's Health Study, a randomized, double-blind, placebo-controlled trial of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer.The association of physical activity and BMI with high-sensitivity C-reactive protein (CRP), fibrinogen, soluble intracellular adhesion molecule 1 (ICAM-1), homocysteine, low- and high-density lipoprotein (LDL and HDL) cholesterol, total cholesterol, apolipoprotein A-1 and B100, lipoprotein(a), and creatinine.Lower levels of physical activity and higher levels of BMI were independently associated (P for trend <.001) with adverse levels of nearly all lipid and inflammatory biomarkers. High BMI showed stronger associations with these biomarkers than physical inactivity. For example, using the reference group of physically active, normal weight women (energy expenditure > or =1000 kcal/week; BMI, 18.5-24.9) and adjusting for age, race, smoking, blood pressure, diabetes, menopausal status, and hormone use, the odds ratios (95% confidence intervals [CIs]) for having CRP >3 mg/L were: for inactive, normal weight women 1.26 (1.15-1.37); active, overweight 2.68 (2.41-2.98); inactive, overweight 3.11 (2.84-3.41); active, obese 8.25 (7.15-9.51); and inactive, obese 9.86 (8.84-10.99). In similar analyses, the odds ratios (95% CIs) for having HDL cholesterol <50 mg/dL were 1.20 (1.11-1.30); 2.25 (2.04-2.49); 2.62 (2.41-2.85); 4.21 (3.68-4.81); and 5.27 (4.77-5.84), respectively, and for having apolipoprotein B100 >120 mg/dL they were 1.21 (1.11-1.33); 1.86 (1.66-2.08); 2.06 (1.88-2.67); 2.35 (2.04-2.70); and 2.33 (2.09-2.59). Fibrinogen, ICAM-1, apolipoprotein A1, total cholesterol, and LDL cholesterol showed similar associations. By contrast, homocysteine, lipoprotein (a), and creatinine showed weak or nonsignificant associations.High BMI was more strongly related to adverse cardiovascular biomarker levels than physical inactivity. However, within BMI categories, physical activity was generally associated with more favorable cardiovascular biomarker levels than inactivity.
PRIMA-1Met/APR-246 Induces Apoptosis and Tumor Growth Delay in Small Cell Lung Cancer Expressing Mutant p53
Authors: Roza Zandi, Galina Selivanova, Camilla Laulund Christensen, Thomas Alexander Gerds, Berthe Marie Willumsen, Hans Skovgaard Poulsen
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Small cell lung cancer (SCLC) is a highly malignant disease with poor prognosis, necessitating the need to develop new and efficient treatment modalities. PRIMA-1Met (p53-dependent reactivation of massive apoptosis), also known as APR-246, is a small molecule, which restores tumor suppressor function to mutant p53 and induces cancer cell death in various cancer types. Since p53 is mutated in more than 90% of SCLC, we investigated the ability of PRIMA-1Met to induce apoptosis and inhibit tumor growth in SCLC with different p53 mutations. Experimental Design: The therapeutic effect of PRIMA-1Met/APR-246 was studied in SCLC cells in vitro using cell viability assay, fluorescence-activated cell-sorting analysis, p53 knockdown studies, and Western blot analyses. The antitumor potential of PRIMA-1Met/APR-246 was further evaluated in two different SCLC xenograft models. Results: PRIMA-1Met/APR-246 efficiently inhibited the growth of the SCLC cell lines expressing mutant p53 in vitro and induced apoptosis, associated with increased fraction of cells with fragmented DNA, caspase-3 activation, PARP cleavage, Bax and Noxa upregulation and Bcl-2 downregulation in the cells. The growth suppressive effect of PRIMA-1Met/APR-246 was markedly reduced in SCLC cell lines transfected with p53 siRNA, supporting the role of mutant p53 in PRIMA-1Met/APR-246-induced cell death. Moreover, in vivo studies showed significant antitumor effects of PRIMA-1Met after i.v. injection in SCLC mouse models with no apparent toxicity. Conclusion: This study is the first to show the potential use of p53-reactivating molecules such as PRIMA-1Met/APR-246 for the treatment of SCLC. Clin Cancer Res; 17(9); 2830–41. ©2011 AACR.
Changes in protein expression during honey bee larval development
Authors: Queenie WT Chan, Leonard J Foster
Journal: Genome biology (2008)

Abstract Background The honey bee ( Apis mellifera ), besides its role in pollination and honey production, serves as a model for studying the biochemistry of development, metabolism, and immunity in a social organism. Here we use mass spectrometry-based quantitative proteomics to quantify nearly 800 proteins during the 5- to 6-day larval developmental stage, tracking their expression profiles. Results We report that honey bee larval growth is marked by an age-correlated increase of protein transporters and receptors, as well as protein nutrient stores, while opposite trends in protein translation activity and turnover were observed. Levels of the immunity factors prophenoloxidase and apismin are positively correlated with development, while others surprisingly were not significantly age-regulated, suggesting a molecular explanation for why bees are susceptible to major age-associated bee bacterial infections such as American Foulbrood or fungal diseases such as chalkbrood. Previously unreported findings include the reduction of antioxidant and G proteins in aging larvae. Conclusion These data have allowed us to integrate disparate findings in previous studies to build a model of metabolism and maturity of the immune system during larval development. This publicly accessible resource for protein expression trends will help generate new hypotheses in the increasingly important field of honey bee research.
Advanced Glycation End Products
Authors: Alison Goldin, Joshua A. Beckman, Ann Marie Schmidt, Mark A. Creager
Journal: Circulation (2006)

Advanced glycation end products (AGEs) are proteins or lipids that become glycated after exposure to sugars. AGEs are prevalent in the diabetic vasculature and contribute to the development of atherosclerosis. The presence and accumulation of AGEs in many different cell types affect extracellular and intracellular structure and function. AGEs contribute to a variety of microvascular and macrovascular complications through the formation of cross-links between molecules in the basement membrane of the extracellular matrix and by engaging the receptor for advanced glycation end products (RAGE). Activation of RAGE by AGEs causes upregulation of the transcription factor nuclear factor-κB and its target genes. Soluble AGEs activate monocytes, and AGEs in the basement membrane inhibit monocyte migration. AGE-bound RAGE increases endothelial permeability to macromolecules. AGEs block nitric oxide activity in the endothelium and cause the production of reactive oxygen species. Because of the emerging evidence about the adverse effects of AGEs on the vasculature of patients with diabetes, a number of different therapies to inhibit AGEs are under investigation.
Polymorphisms of type I interferon receptor 1 promoter and their effects on chronic hepatitis B virus infection
Authors: Jie Zhou, Liwei Lu, Man-Fung Yuen, Ting-Wa Lam, Chi-Ping Chung, Chun-Lit Lam, Bin Zhang, Song Wang, Yu Chen, Sharon HW Wu, Vincent KM Poon, Fai Ng, Chris CS Chan, Shibo Jiang, Kwok-Yung Yuen, Bo-Jian Zheng
Journal: Journal of Hepatology (2006)
Trabecular bone mass and bone formation are preserved after limb immobilisation in p53 null mice
Authors: R Okazaki
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objectives:</b> To determine whether disruption of the p53 gene leads to preservation of trabecular bone volume (BV) after limb immobilisation. <b>Materials and methods:</b> Tibias of immobilised hind limbs of p53 gene knockout (p53<sup>−/−</sup>) and wild-type (p53<sup>+/+</sup>) mice were compared. Right knee joints of 8 week old mice were immobilised in full extension for 7 days. Trabecular structure and bone formation were similar in the p53<sup>−/−</sup> and p53<sup>+/+</sup> control groups. <b>Results:</b> Immobilisation significantly reduced BV to 77% of the control in p53<sup>+/+</sup> mice, but no change was noted in p53<sup>−/−</sup> mice. After immobilisation, bone formation rate was significantly reduced in p53<sup>+/+</sup> but not in p53<sup>−/−</sup> mice. In bone marrow cell cultures the numbers of alkaline phosphatase positive colony forming units-fibroblastic and mineralised nodules were significantly reduced by immobilisation in p53<sup>+/+</sup> but not in p53<sup>−/−</sup> mice. Immobilisation enhanced p53 mRNA expression in marrow cells of p53<sup>+/+</sup> mice and increased terminal dUTP nick end labelling positive osteocytes and marrow cells in p53<sup>+/+</sup> but not in p53<sup>−/−</sup> mice. Lack of p53 in immobilised mice was associated with preservation of trabecular bone mass and bone formation and suppression of significant apoptosis of marrow cells. <b>Conclusion:</b> Disruption of the p53 gene preserves trabecular bone mass and leads to bone formation after limb immobilisation.
THE EFFECT OF 5-HYDROXYTRYPTAMINE ON THE COTTON PELLET LOCAL INFLAMMATORY RESPONSE IN THE RAT
Authors: Joseph R. Bianchine, Norman R. Eade
Journal: The Journal of Experimental Medicine (1967)

The cotton pellet technique was used to evaluate the effect of 5-HT and certain related compounds on granuloma formation in the rat. 5-HT (10 mg/kg) significantly decreased granuloma formation, significantly increased adrenal weight, and significantly decreased thymus weight in normal rats, and significantly decreased granuloma formation and thymus weight in sham-operated rats. On the other hand, 5-HT (10 mg/kg) significantly increased granuloma weight in adrenalectomized rats. Methysergide (1 mg/kg) blocked the inhibitory effect of 5-HT on granuloma formation as well as the changes in weight of adrenal and thymus glands. 5-HIAA (11 mg/kg) and 5-HTP (13 mg/kg) failed to alter granuloma formation.
Twist mediates suppression of inflammation by type I IFNs and Axl
Authors: M. Nusrat Sharif, Dražen Šošić, Carla V. Rothlin, Erin Kelly, Greg Lemke, Eric N. Olson, Lionel B. Ivashkiv
Journal: The Journal of Experimental Medicine (2006)

Type I interferons (IFNs) are pleiotropic cytokines with antiviral and immunomodulatory properties. The immunosuppressive actions of type I IFNs are poorly understood, but IFN-mediated suppression of TNFα production has been implicated in the regulation of inflammation and contributes to the effectiveness of type I IFNs in the treatment of certain autoimmune and inflammatory diseases. In this study, we investigated mechanisms by which type I IFNs suppress induction of TNFα production by immune complexes, Fc receptors, and Toll-like receptors. Suppression of TNFα production was mediated by induction and activation of the Axl receptor tyrosine kinase and downstream induction of Twist transcriptional repressors that bind to E box elements in the TNF promoter and suppress NF-κB–dependent transcription. Twist expression was activated by the Axl ligand Gas6 and by protein S and apoptotic cells. These results implicate Twist proteins in regulation of TNFα production by antiinflammatory factors and pathways, and provide a mechanism by which type I IFNs and Axl receptors suppress inflammatory cytokine production.
PharmGKB Update: III. Genetic Variants of SLC22A1, Solute Carrier Family 22 (Organic Cation Transporter), Member 1
Authors: Yan Shu, Maya K. Leabman, Bo Feng, Lara M. Mangravite, Conrad C. Huang, Doug Stryke, Michiko Kawamoto, Susan J. Johns, Joseph DeYoung, Elaine Carlson, Thomas E. Ferrin, Ira Herskowitz, Kathleen M. Giacomini
Journal: Pharmacological Reviews (2004)

Category: Genotype PharmGKB Submission Number: PS203001 <http://www.pharmgkb.org/do/serve?objId=PA329&objCls=Gene> Date of Submission: June 16, 2003 Project: Pharmacogenetics of Membrane Transporters HGNC Symbol: SLC22A1 HGNC Name: solute carrier family 22 (organic cation transporter), member 1
Ascorbic acid prevents loss of Dlk1-Dio3 imprinting and facilitates generation of all–iPS cell mice from terminally differentiated B cells
Authors: Matthias Stadtfeld, Effie Apostolou, Francesco Ferrari, Jiho Choi, Ryan M Walsh, Taiping Chen, Steen S K Ooi, Sang Yong Kim, Timothy H Bestor, Toshi Shioda, Peter J Park, Konrad Hochedlinger
Journal: Nature Genetics (2012)
Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial
Authors: Lee S Schwartzberg, Manuel R Modiano, Bernardo L Rapoport, Martin R Chasen, Cesare Gridelli, Laszlo Urban, Allen Poma, Sujata Arora, Rudolph M Navari, Ian D Schnadig
Journal: The Lancet Oncology (2015)
Cd8+ but Not Cd8− Dendritic Cells Cross-Prime Cytotoxic T Cells in Vivo
Authors: Joke M.M. den Haan, Sophie M. Lehar, Michael J. Bevan
Journal: The Journal of Experimental Medicine (2000)

Bone marrow–derived antigen-presenting cells (APCs) take up cell-associated antigens and present them in the context of major histocompatibility complex (MHC) class I molecules to CD8+ T cells in a process referred to as cross-priming. Cross-priming is essential for the induction of CD8+ T cell responses directed towards antigens not expressed in professional APCs. Although in vitro experiments have shown that dendritic cells (DCs) and macrophages are capable of presenting exogenous antigens in association with MHC class I, the cross-presenting cell in vivo has not been identified. We have isolated splenic DCs after in vivo priming with ovalbumin-loaded β2-microglobulin–deficient splenocytes and show that they indeed present cell-associated antigens in the context of MHC class I molecules. This process is transporter associated with antigen presentation (TAP) dependent, suggesting an endosome to cytosol transport. To determine whether a specific subset of splenic DCs is involved in this cross-presentation, we negatively and positively selected for CD8− and CD8+ DCs. Only the CD8+, and not the CD8−, DC subset demonstrates cross-priming ability. FACS® studies after injection of splenocytes loaded with fluorescent beads showed that 1 and 0.6% of the CD8+ and the CD8− DC subsets, respectively, had one or more associated beads. These results indicate that CD8+ DCs play an important role in the generation of cytotoxic T lymphocyte responses specific for cell-associated antigens.