tbuckley/cabot-search huggingface dataset:
Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN
Authors: Michael Luig, Malte A. Kluger, Boeren Goerke, Matthias Meyer, Anna Nosko, Isabell Yan, Jürgen Scheller, Hans-Willi Mittrücker, Stefan Rose-John, Rolf A.K. Stahl, Ulf Panzer, Oliver M. Steinmetz
Journal: Journal of the American Society of Nephrology (2015)

IL-6 can mediate proinflammatory effects, and IL-6 receptor (IL-6R) blockade as a treatment for inflammatory diseases has entered clinical practice. However, opposing effects of IL-6 have been observed in models of GN. Although IL-6 is proinflammatory in murine lupus nephritis, protective effects have been observed for IL-6 in the nephrotoxic nephritis (NTN) model of acute crescentic GN. In light of the potential dangers of IL-6-directed treatment, we studied the mechanisms underlying the contradictory findings in GN. IL-6 can signal through the membrane-bound IL-6R, which is expressed only on hepatocytes and certain leukocytes (classic), or through the soluble IL-6R, which binds the ubiquitously expressed gp130 (alternative). Preemptive treatment of mice with anti-IL-6R or anti-IL-6 worsened NTN, whereas selective blockade of alternative IL-6 signaling by the fusion protein sgp130Fc did not. FACS analysis of mouse spleen cells revealed proinflammatory macrophages express the highest levels of IL-6Rα, and in vitro treatment with IL-6 blocked macrophage proliferation. Furthermore, proinflammatory macrophages were expanded during inflammation in IL-6(-/-) mice. Late application of anti-IL-6 after establishment of adaptive nephritogenic immunity was sufficient to aggravate NTN within 2.5 days, a period when macrophages are active. Finally, NTN was aggravated in mice with macrophage-specific impairment of IL-6 classic signaling, coincident with enhanced macrophage proliferation and accumulation in the kidney. Our data thus reveal a novel mechanism in which IL-6-mediated dampening of macrophage activation protects tissues from overshooting immune responses. This finding has important implications for potential IL-6-directed therapies and supports the careful choice of recipient patients and timing.
Degradation of connective tissue matrices by macrophages. III. Morphological and biochemical studies on extracellular, pericellular, and intracellular events in matrix proteolysis by macrophages in culture.
Authors: Z Werb, D F Bainton, P A Jones
Journal: The Journal of Experimental Medicine (1980)

We have shown that macrophages in culture degrade the glycoproteins and amorphous elastin of insoluble extracellular matrices. Ultrastructural observation of the macrophage-matrix interaction revealed that connective tissue macromolecules were solubilized from the matrix extracellularly. At least part of the matrix breakdown was localized to the immediate vicinity of the cells, as shown by morphological and biochemical studies, although the rate of degradation correlated closely with the secretion of proteinases by various inflammatory stimuli in vivo, by glucocorticoids, prostaglandin E2 or colchicine, or by phagocytosis of latex, zymosan, or cholesterol-albumin complexes in culture was reflected in altered rates of glycoprotein and elastin degradation by the macrophages. Alteration of endocytosis and lysosomal digestion by cytochalasin B, NH4Cl, and proteinase inhibitors did not decrease the overall rate of matrix solubilization, but reduced the processing of the matrix fragments to peptides. Therefore, extracellular, pericellular, and lysosomal events each contribute to degradation of extracellular matrix macromolecules by inflammatory macrophages.
<i>PDGFRA</i> Mutations in Gastrointestinal Stromal Tumors: Frequency, Spectrum and In Vitro Sensitivity to Imatinib
Authors: Christopher L. Corless, Arin Schroeder, Diana Griffith, Ajia Town, Laura McGreevey, Patina Harrell, Sharon Shiraga, Troy Bainbridge, Jason Morich, Michael C. Heinrich
Journal: Journal of Clinical Oncology (2005)

Purpose Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT tyrosine kinase, which is a target for the kinase inhibitor imatinib. A subset of GISTs, however, contains mutations in the homologous kinase platelet derived growth factor receptor alpha (PDGFRA), and the most common of these mutations is resistant to imatinib in vitro. Little is known of the other types of PDGFRA mutations that occur in GISTs. Materials and Methods We determined the KIT and PDGFRA mutation status of 1,105 unique GISTs using a combination of denaturing high-performance liquid chromatography and direct sequencing. Results There were 80 tumors (7.2%) with a PDGFRA mutation: 66 in exon 18, 11 in exon 12, and three in exon 14. Transient expression of representative PDGFRA isoforms in CHO cells revealed imatinib sensitivity of exon 12 mutations (SPDHE566-571R and insertion ER561-562) and an exon 14 substitution (N659K). However, most isoforms with a substitution involving codon D842 in exon 18 (D842V, RD841-842KI, DI842-843IM) were resistant to the drug, with the exception of D842Y. Interestingly, other mutations in exon 18 (D846Y, N848K, Y849K and HDSN845-848P) were all imatinib sensitive. Proliferation studies with BA/F3 cell lines stably expressing selected PDGFRA mutant isoforms supported these findings. Conclusion Including our cases, there are 289 reported PDGFRA-mutant GISTs, of which 181 (62.6%) had the imatinib-resistant substitution D842V. However, our findings suggest that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these tumors.
Mining physical protein-protein interactions from the literature
Authors: Minlie Huang, Shilin Ding, Hongning Wang, Xiaoyan Zhu
Journal: Genome biology (2008)

Deciphering physical protein-protein interactions is fundamental to elucidating both the functions of proteins and biological processes. The development of high-throughput experimental technologies such as the yeast two-hybrid screening has produced an explosion in data relating to interactions. Since manual curation is intensive in terms of time and cost, there is an urgent need for text-mining tools to facilitate the extraction of such information. The BioCreative (Critical Assessment of Information Extraction systems in Biology) challenge evaluation provided common standards and shared evaluation criteria to enable comparisons among different approaches. During the benchmark evaluation of BioCreative 2006, all of our results ranked in the top three places. In the task of filtering articles irrelevant to physical protein interactions, our method contributes a precision of 75.07%, a recall of 81.07%, and an AUC (area under the receiver operating characteristic curve) of 0.847. In the task of identifying protein mentions and normalizing mentions to molecule identifiers, our method is competitive among runs submitted, with a precision of 34.83%, a recall of 24.10%, and an F1 score of28.5%. In extracting protein interaction pairs, our profile-based method was competitive on the SwissProt-only subset (precision = 36.95%, recall = 32.68%, and F1 score = 30.40%) and on the entire dataset (30.96%, 29.35%, and26.20%, respectively). From the biologist's point of view, however, these findings are far from satisfactory. The error analysis presented in this report provides insight into how performance could be improved: three-quarters of false negatives were due to protein normalization problems (532/698), and about one-quarter were due to problems with correctly extracting interactions for this system. We present a text-mining framework to extract physical protein-protein interactions from the literature. Three key issues are addressed, namely filtering irrelevant articles, identifying protein names and normalizing them to molecule identifiers, and extracting protein-protein interactions. Our system is among the top three performers in the benchmark evaluation of BioCreative 2006. The tool will be helpful for manual interaction curation and can greatly facilitate the process of extracting protein-protein interactions.
Malignant melanoma in patients with hereditary nonpolyposis colorectal cancer
Authors: G. Ponti, L. Losi, G. Pellacani, L. Wannesson, A.M. Cesinaro, T. Venesio, C. Petti, S. Seidenari
Journal: British Journal of Dermatology (2008)

Malignant melanoma (MM) is the most aggressive skin cancer. Most MMs are sporadic, and in this setting an association with mismatch repair (MMR) gene mutations, typical of hereditary nonpolyposis colorectal cancer (HNPCC) tumours, has been proposed.To characterize clinically and/or by molecular biology the patients with MM belonging to a cohort of 60 kindreds with HNPCC. Methods Patients with HNPCC with a diagnosis of MM were studied by immunohistochemistry (IHC) on tumour tissue using antibodies to MLH1, MSH2, p16, beta-catenin and E-cadherin, and by direct sequencing of MMR genes on germline DNA, and BRAF and NRAS on somatic DNA extracted from MM.Nine cutaneous MMs were detected in the tumour spectrum of eight families with HNPCC. The median age at diagnosis was 46 years. In one HNPCC family the diagnosis of MM was made in two first-degree relatives fitting the clinical definition of familial melanoma. IHC and sequencing analysis showed an MSH2 mutation in one patient with MM.Dermatological surveillance should be recommended to families in which MM is diagnosed in at least one member, especially at a young age. The combination of MMR gene mutations and abnormalities of p16 or other molecular pathways is needed to induce melanocytic carcinogenesis in a familial setting as well as in sporadic MM.
Monitoring genotoxic exposure in uranium miners.
Authors: R J Srám, B Binková, L Dobiás, P Rössner, J Topinka, D Veselá, D Veselý, J Stejskalová, H Bavorová, V Rericha
Journal: Environmental Health Perspectives (1993)

Recent data from deep uranium mines in Czechoslovakia indicated that in addition to radon daughter products, miners are also exposed to chemical mutagens. Mycotoxins were identified as a possible source of mutagenicity present in the mines. Various methods of biomonitoring were used to examine three groups of miners from different uranium mines. Cytogenetic analysis of peripheral lymphocytes, unscheduled DNA synthesis (UDS) in lymphocytes, and lipid peroxidation (LPO) in both plasma and lymphocytes were studied on 66 exposed miners and 56 controls. Throat swabs were taken from 116 miners and 78 controls. Significantly increased numbers of aberrant cells were found in all groups of miners, as well as decreased UDS values in lymphocytes and increased LPO plasma levels in comparison to controls. Molds were detected in throat swabs from 27% of miners, and 58% of these molds were embryotoxic. Only 5% of the control samples contained molds and none of them was embryotoxic. The following mycotoxins were isolated from miners' throat swab samples: rugulosin, sterigmatocystin, mycophenolic acid, brevianamid A, citreoviridin, citrinin, penicilic acid, and secalonic acid. These data suggest that mycotoxins are a genotoxic factor affecting uranium miners.
High Level of Burnout in Intensivists
Authors: Nathalie Embriaco, Elie Azoulay, Karine Barrau, Nancy Kentish, Frédéric Pochard, Anderson Loundou, Laurent Papazian
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Professional burnout is a psychological syndrome arising in response to chronic interpersonal stressors on the job. There is the perception that intensivists are particularly exposed to stress because lives are literally in their hands.To evaluate the prevalence and associated factors (patients or organization) of burnout among physicians working in intensive care units (ICUs) (including interns, residents, fellows, and attending physicians).A 1-day national survey was conducted in adult ICUs in French public hospitals.The level of burnout was evaluated on the basis of the Maslach Burnout Inventory (MBI).A total of 189 ICUs participated and 978 surveys were returned (82.3% response rate). A high level of burnout was identified in 46.5% of the respondents. Ordinal logistic regression showed that female sex (odds ratio, 1.58; 95% confidence interval, 1.09 to 2.30) was independently associated with a higher MBI score. Whereas no factor related to the severity of illness of patients was retained by the model, organizational factors were strongly associated with a higher MBI score. Workload (the number of night shifts per month, a long period of time from the last nonworking week, night shift the day before the survey) and impaired relationships (such as conflict with another colleague intensivist, and/or with a nurse) were the variables independently associated with a higher MBI score. In contrast, the quality of the relationships with chief nurses and nurses was associated with a lower MBI score.Approximately one-half of the intensivists presented a high level of burnout. Organizational factors, but not factors related to the patients, appeared to be associated with burnout.
Heparan Sulfate Proteoglycans Function as Receptors for Fibroblast Growth Factor-2 Activation of Extracellular Signal–Regulated Kinases 1 and 2
Authors: Ceres C. Chua, Nader Rahimi, Kimberly Forsten-Williams, Matthew A. Nugent
Journal: Circulation Research (2003)

Fibroblast growth factor-2 (FGF2) activates the extracellular signal–regulated kinases 1 and 2 (ERK1/2) through its specific receptors. Interaction of FGF2 with cell-surface heparan sulfate proteoglycans has also been suggested to induce intracellular signals. Thus, we investigated whether FGF2 can stimulate ERK1/2 activation through heparan sulfate proteoglycans using mechanisms that do not depend on receptor activation in vascular smooth muscle cells. The activation of FGF receptors was inhibited by treating cells with 5′-deoxy-5′methyl-thioadenosine and by expressing truncated dominant-negative FGF receptors. In both cases, FGF2 was able to stimulate the phosphorylation of ERK1/2 despite the absence of detectable FGF receptor tyrosine kinase activity. The FGF2 activation of ERK1/2 in the absence of receptor activity was completely dependent on heparan sulfate, because this activity was abolished by heparinase III digestion of the cells. In contrast, heparinase III treatment of control cells, with functional FGF receptors, showed only slight changes in FGF2-mediated ERK1/2 activation kinetics. Thus, in addition to serving as coreceptors for FGF receptor activation, heparan sulfate proteoglycans might also function directly as receptors for FGF2-induced ERK1/2 activation. Activation of ERK1/2 via cell-surface proteoglycans could have significant biological consequences, potentially directing cell response toward growth, migration, or differentiation.
In Vivo Myocardial Protection From Ischemia/Reperfusion Injury by the Peroxisome Proliferator–Activated Receptor-γ Agonist Rosiglitazone
Authors: Tian-li Yue, Jun Chen, Weike Bao, Padma K. Narayanan, Antoine Bril, Wen Jiang, Paul G. Lysko, Juan-Li Gu, Rogely Boyce, Dawn M. Zimmerman, Timothy K. Hart, Robin E. Buckingham, Eliot H. Ohlstein
Journal: Circulation (2001)

Diabetes is associated with increased risk of mortality as a consequence of acute myocardial infarction. This study determined whether rosiglitazone (ROSI) could reduce myocardial infarction after ischemia/reperfusion injury.Male Lewis rats were anesthetized, and the left anterior descending coronary artery was ligated for 30 minutes. After reperfusion for 24 hours, the ischemic and infarct sizes were determined. ROSI at 1 and 3 mg/kg IV reduced infarct size by 30% and 37%, respectively (P<0.01 versus vehicle). Pretreatment with ROSI (3 mg. kg(-1). d(-1) PO) for 7 days also reduced infarct size by 24% (P<0.01). ROSI also improved ischemia/reperfusion-induced myocardial contractile dysfunction. Left ventricular systolic pressure and positive and negative maximal values of the first derivative of left ventricular pressure (dP/dt) were significantly improved in ROSI-treated rats. ROSI reduced the accumulation of neutrophils and macrophages in the ischemic heart by 40% and 43%, respectively (P<0.01). Ischemia/reperfusion induced upregulation of CD11b/CD18 and downregulation of L-selectin on neutrophils and monocytes; these effects were significantly attenuated in ROSI-treated animals. Likewise, intercellular adhesion molecule-1 expression in ischemic hearts was markedly diminished by ROSI, as was the ischemia/reperfusion-stimulated upregulation of monocyte chemoattractant protein-1.ROSI reduced myocardial infarction and improved contractile dysfunction caused by ischemia/reperfusion injury. The cardioprotective effect of ROSI was most likely due to inhibition of the inflammatory response.
Direct‐Write Assembly of 3D Silk/Hydroxyapatite Scaffolds for Bone Co‐Cultures
Authors: Lin Sun, Sara T. Parker, Daisuke Syoji, Xiuli Wang, Jennifer A. Lewis, David L. Kaplan
Journal: Advanced Healthcare Materials (2012)

3D silk/HA microperiodic scaffolds for bone tissue engineering and angiogenesis are fabricated by direct-write assembly. This approach can be used to control filament and spacing size in the scaffold to allow investigation of the effect of scaffold architecture on osteogenesis and vessel-like structure formation from stem cells and endothelial cells. Detailed facts of importance to specialist readers are published as "Supporting Information". Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Removal of Aflatoxin B&lt;sub&gt;1&lt;/sub&gt;-DNA Adducts and In Vitro Transformation in Mouse Embryo Fibroblasts C3H/10T½&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: P A Amstad, T V Wang, P A Cerutti
Journal: JNCI Journal of the National Cancer Institute (1983)

The mechanism of in vitro transformation of the mouse embryo fibroblast C3H/10T½ clone 8 by aflatoxin B1 (AFB1) was studied in confluent holding (CH) experiments. Confluent cultures of C3H/10T½ cells were treated with AFB1 for 16 hours. and the DNA adduct composition and concentration were determined by chromatographic procedures after 0, 8, 16, and 40 hours of CH when the cells were replated at low density for the expression of their colony-forming ability and the formation of transformed foci. Total adduct concentration and the concentration of the major primary adduct 2.3-dihydro-2-(N7-guanyl)-3-hydroxyaflatoxin B1 (AFB1-N7-Gua) decreased continuously during CH due to spontaneous decomposition and probably also due to enzymatic repair processes. In contrast. the more chemically stable secondary product 2,3-dihydro-2-(N5-formyl-2′,5′,6′-triamino-4′-oxo- N5-pyrimidyl)-3-hydroxyaflatoxin B1 (AFB1-triamino-Py) accumulated in the DNA and reached its maximum concentration after 16 hours of CH. while the loss of total AFB,-DNA adducts during CH was reflected in recovery of viability. the potential to form transformed foci reached a maximum after 16 hours of CH and then decreased with continued CH below the initial value. Therefore. no simple relationship exists between the concentration of the total adducts AFB1-N7-Gua and AFB1-triamino- Py at the time of release from CH and the potential to form transformed foci. However, DNA lesions or abnormal DNA configurations formed during CH as a consequence of the cellular processing of AFB1-DNA adducts may play a role in the transformation process.
Variation of C-Reactive Protein Levels in Adolescents
Authors: Emma K. Larkin, Carol L. Rosen, H. Lester Kirchner, Amy Storfer-Isser, Judith L. Emancipator, Nathan L. Johnson, Anna Marie V. Zambito, Russell P. Tracy, Nancy S. Jenny, Susan Redline
Journal: Circulation (2005)

Background— There is increasing evidence that sleep-disordered breathing (SDB) is an independent risk factor for cardiovascular disease (CVD) in adults. C-reactive protein (CRP), a marker of systemic inflammation, is an important predictor of future cardiovascular events. The goal of this study was to quantify the associations of SDB, sleep duration, and CRP in adolescents to better understand the role of SDB in CVD risk. Methods and Results— Adolescents (n=143; age, 13 to 18 years; 36% black; 50% female) with a wide range of SDB severity underwent polysomnography and measurement of high-sensitivity CRP. SDB was quantified with the apnea hypopnea index (AHI) and oxygen desaturation measures. Sleep duration was estimated from 7-day actigraphy. The independent and dose-response associations of SDB with CRP were addressed through linear mixed-effects models. Forty-eight percent were overweight or obese, and 12% had SDB (AHI ≥5). CRP levels varied with increasing body mass index and SDB. After adjustment for body mass index , age, sex, and race, mean CRP levels were 0.50, 0.43, 0.97, and 1.66 mg/L for SDB severity levels of AHI &lt;1, 1 to 4.9, 5 to 14.9, and ≥15, respectively ( P =0.0049, AHI ≥15 versus &lt;1). Adjusted mean CRP levels demonstrated a dose response with SDB above a threshold AHI of 5. This association was partially explained by overnight hypoxemia and less so by sleep duration. Conclusions— In adolescents free of known CVD, an AHI ≥5 is associated with increasing levels of CRP, suggesting that pediatric SDB may confer additional CVD risk beyond that of obesity.
PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel and CMF versus a standard-dosed epirubicin/cyclophosphamide followed by paclitaxel ± darbepoetin alfa in primary breast cancer—results at the time of surgery
Authors: M. Untch, P.A. Fasching, G.E. Konecny, F. von Koch, U. Conrad, W. Fett, C. Kurzeder, H.-J. Lück, E. Stickeler, H. Urbaczyk, B. Liedtke, C. Salat, N. Harbeck, V. Müller, M. Schmidt, S. Hasmüller, M. Lenhard, T. Schuster, V. Nekljudova, A. Lebeau, S. Loibl, G. von Minckwitz
Journal: Annals of Oncology (2011)
Developmental Neurocircuitry of Motivation in Adolescence: A Critical Period of Addiction Vulnerability
Authors: R. Andrew Chambers, Jane R. Taylor, Marc N. Potenza
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Epidemiological studies indicate that experimentation with addictive drugs and onset of addictive disorders is primarily concentrated in adolescence and young adulthood. The authors describe basic and clinical data supporting adolescent neurodevelopment as a biologically critical period of greater vulnerability for experimentation with substances and acquisition of substance use disorders. METHOD: The authors reviewed recent literature regarding neurocircuitry underlying motivation, impulsivity, and addiction, with a focus on studies investigating adolescent neurodevelopment. RESULTS: Adolescent neurodevelopment occurs in brain regions associated with motivation, impulsivity, and addiction. Adolescent impulsivity and/or novelty seeking as a transitional trait behavior can be explained in part by maturational changes in frontal cortical and subcortical monoaminergic systems. These developmental processes may advantageously promote learning drives for adaptation to adult roles but may also confer greater vulnerability to the addictive actions of drugs. CONCLUSIONS: An exploration of developmental changes in neurocircuitry involved in impulse control has significant implications for understanding adolescent behavior, addiction vulnerability, and the prevention of addiction in adolescence and adulthood.