tbuckley/cabot-search huggingface dataset:
Interleukins in Atherosclerosis: Molecular Pathways and Therapeutic Potential
Authors: Jan H. Von der Thüsen, Johan Kuiper, Theo J. C. Van Berkel, Erik A. L. Biessen
Journal: Pharmacological Reviews (2003)

Interleukins are considered to be key players in the chronic vascular inflammatory response that is typical of atherosclerosis. Thus, the expression of proinflammatory interleukins and their receptors has been demonstrated in atheromatous tissue, and the serum levels of several of these cytokines have been found to be positively correlated with (coronary) arterial disease and its sequelae. In vitro studies have confirmed the involvement of various interleukins in pro-atherogenic processes, such as the up-regulation of adhesion molecules on endothelial cells, the activation of macrophages, and smooth muscle cell proliferation. Furthermore, studies in mice deficient or transgenic for specific interleukins have demonstrated that, whereas some interleukins are indeed intrinsically pro-atherogenic, others may have anti-atherogenic qualities. As the roles of individual interleukins in atherosclerosis are being uncovered, novel anti-atherogenic therapies, aimed at the modulation of interleukin function, are being explored. Several approaches have produced promising results in this respect, including the transfer of anti-inflammatory interleukins and the administration of decoys and antibodies directed against proinflammatory interleukins. The chronic nature of the disease and the generally pleiotropic effects of interleukins, however, will demand high specificity of action and/or effective targeting to prevent the emergence of adverse side effects with such treatments. This may prove to be the real challenge for the development of interleukin-based anti-atherosclerotic therapies, once the mediators and their targets have been delineated.
St. Andrew's Ambulance Association experience at Ibrox and Hampden Parks.
Authors: R Scott, N Burns, G McIlwraith, I Kirkwood, A Petrie
Journal: British Journal of Sports Medicine (1991)

Recent major accidents at football grounds have greatly increased government and public awareness of the potentially lethal environment of soccer grounds in the UK.In the final recommendations of the official report on the Hillsborough disaster it is stated that regular liaison of the emergency services, specifically police, fire and ambulance, at designated sports grounds is extremely important.In his report', Lord Taylor does not include the first aiders in this particular context, but in a subsequent paragraph he advocates the presence of first aiders at a rate of 1 per 1000 spectators (Recommendation 64).First aiders at football grounds are present on a voluntary basis and are organized by their parent organizations, namely St. Andrew's Ambulance Association in Scotland, St. John Ambulance Associ- ation in England, Wales and Northern Ireland and the British Red Cross in all four countries.It is the first aiders who initiate the primary medical response in the event of a major incident, as was clearly seen on the television recordings of the Hillsborough disaster.Training and recruitment of first aid personnel Under the auspices of all three parent organizations the first aiders undergo a series of lectures and practical demonstrations by first aid instructors and by members of the medical profession.After passing the necessary examination at the end of the course, these lay persons are invited to become full members of a corps company or its equivalent where they are taught procedures of transportation of casualties, advanced techniques, and response of first aiders acting in partnership with other emergency workers.In addition, they are required to update their first aid certificates regularly to ensure that they are aware of new equipment and that their knowledge is satisfac- tory and current.
Epitope-Tagged Pkhd1 Tracks the Processing, Secretion, and Localization of Fibrocystin
Authors: Jason L. Bakeberg, Rachaneekorn Tammachote, John R. Woollard, Marie C. Hogan, Han-Fang Tuan, Ming Li, Jan M. van Deursen, Yanhong Wu, Bing Q. Huang, Vicente E. Torres, Peter C. Harris, Christopher J. Ward
Journal: Journal of the American Society of Nephrology (2011)

Mutations in the PKHD1 gene, which encodes fibrocystin, cause autosomal recessive polycystic kidney disease (ARPKD). Unfortunately, the lack of specific antibodies to the mouse protein impairs the study of splicing, post-translational processing, shedding, and temporal and spatial expression of endogenous fibrocystin at the cellular and subcellular level. Here, we report using a knock-in strategy to generate a null Pkhd1 strain and a strain that expresses fibrocystin along with two SV5-Pk epitope tags engineered in-frame into the third exon, immediately C-terminal to the signal-peptide cleavage site in a poorly conserved region. By 6 mo of age, the Pkhd1-null mouse develops massive cystic hepatomegaly and proximal tubule dilation, whereas the mouse with epitope-tagged fibrocystin has histologically normal liver and kidneys at 14 mo. Although Pkhd1 was believed to generate many splice forms, our western analysis resolved fibrocystin as a 500 kD product without other forms in the 15-550 kD range. Western analysis also revealed that exosome-like vesicles (ELVs) secrete the bulk of fibrocystin in its mature cleaved form, and scanning electron microscopy identified that fibrocystin on ELVs attached to cilia. Furthermore, the addition of ELVs with epitope-tagged fibrocystin to wild-type cells showed that label transferred to primary cilia within 5 min. In summary, tagging of the endogenous Pkhd1 gene facilitates the study of the glycosylation, proteolytic cleavage, and shedding of fibrocystin.
Temporal Trends in Cause-Specific Late Mortality Among 5-Year Survivors of Childhood Cancer
Authors: Gregory T. Armstrong, Zhenyu Pan, Kirsten K. Ness, Deokumar Srivastava, Leslie L. Robison
Journal: Journal of Clinical Oncology (2010)

Five-year survival rates for childhood cancer have improved over the past four decades. However, it is unknown whether changes in primary cancer therapy have improved rates of long-term (> 5 years from diagnosis) durable remissions and reduced treatment-related deaths. We investigated changes in patterns of late mortality over time and cause-specific attribution of late-mortality among 5-year survivors.Using data from the Surveillance, Epidemiology and End Results (SEER) population-based registry, we assessed all-cause and cause-specific (recurrence/progression of primary disease, external cause, and nonrecurrence/nonexternal cause) late mortality during four consecutive time periods from 1974 through 2000 among 26,643 5-year survivors of childhood cancer.All-cause late mortality improved during more recent eras, dropping from 7.1% (95% CI, 6.4% to 7.8%) among children diagnosed during 1974 to 1980 to 3.9% (95% CI, 3.3% to 4.4%) among children diagnosed during 1995 to 2000 (P < .001), largely because of reduced mortality from recurrence or progression. While there was no significant reduction in mortality attributable to other health conditions (including treatment-related health conditions), analysis controlling for demographic characteristics identified a trend toward reduced risk during more recent eras (P = .007). Disparity by race/ethnicity was identified, with higher mortality among non-Hispanic blacks than among non-Hispanic whites for all-cause and nonrecurrence/nonexternal -cause late mortality.While overall patterns of mortality from other health conditions do not differ over time, adjustment for demographic characteristics provides evidence that risk of treatment-related mortality may be lower in more recent eras. Disparities in health care utilization among survivors should be explored.
Analysis of variation at transcription factor binding sites in Drosophila and humans
Authors: Mikhail Spivakov, Junaid Akhtar, Pouya Kheradpour, Kathryn Beal, Charles Girardot, Gautier Koscielny, Javier Herrero, Manolis Kellis, Eileen EM Furlong, Ewan Birney
Journal: Genome biology (2012)

Abstract Background Advances in sequencing technology have boosted population genomics and made it possible to map the positions of transcription factor binding sites (TFBSs) with high precision. Here we investigate TFBS variability by combining transcription factor binding maps generated by ENCODE, modENCODE, our previously published data and other sources with genomic variation data for human individuals and Drosophila isogenic lines. Results We introduce a metric of TFBS variability that takes into account changes in motif match associated with mutation and makes it possible to investigate TFBS functional constraints instance-by-instance as well as in sets that share common biological properties. We also take advantage of the emerging per-individual transcription factor binding data to show evidence that TFBS mutations, particularly at evolutionarily conserved sites, can be efficiently buffered to ensure coherent levels of transcription factor binding. Conclusions Our analyses provide insights into the relationship between individual and interspecies variation and show evidence for the functional buffering of TFBS mutations in both humans and flies. In a broad perspective, these results demonstrate the potential of combining functional genomics and population genetics approaches for understanding gene regulation.
Hyperglycemia-Induced Thioredoxin-Interacting Protein Expression Differs in Breast Cancer–Derived Cells and Regulates Paclitaxel IC50
Authors: Francesco Turturro, Gary Von Burton, Ellen Friday
Journal: Clinical Cancer Research (2007)

Abstract Purpose: We studied the hyperglycemia-induced expression of thioredoxin-interacting protein (TXNIP) expression and its relevance on the cytotoxic activity of paclitaxel in mammary epithelial–derived cell lines. Experimental Design: Nontumorigenic cells (MCF10A); tumorigenic, nonmetastatic cells (MCF-7/T47D); and tumorigenic, metastatic cells (MDA-MB-231/MDA-MB-435s) were grown either in 5 or 20 mmol/L glucose chronically. Semiquantitative reverse transcription-PCR was used to assess TXNIP RNA expression in response to glucose. Reactive oxygen species were detected by CM-H2DCFDA (5-6-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate) and measured for mean fluorescence intensity with flow cytometry. Thioredoxin activity was assayed by the insulin disulfide-reducing assay. Proliferation was evaluated using CellTiter96 reagent with 490-nm absorption. Obtained absorbance values were used to calculate the paclitaxel IC50 in 5 or 20 mmol/L glucose using the Chou's dose-effect equation. Results: We show that hyperglycemia by itself affects the level of TXNIP RNA in breast cancer–derived cells. TXNIP RNA level differs between nontumorigenic/nonmetastatic, tumorigenic cells (low TXNIP level), and metastatic cells (high TXNIP level). The differences in TXNIP RNA level, in reactive oxygen species level, and in thioredoxin activity are all related. We further show that hyperglycemia is a favorable condition in increasing the paclitaxel cytotoxicity by causing IC50 3-fold decrease in metastatic breast cancer–derived MDA-MB-231 cells. The increased paclitaxel cytotoxicity is associated with an additive effect on the hyperglycemia-mediated TXNIP expression more evident in conditions of hyperglycemia than normoglycemia. Conclusions: Our study opens a new perspective on the relevance of metabolic conditions of hyperglycemia in the biology and treatment of cancer, particularly in view of the epidemic of diabetes.
Inhibitors of Protein Kinase Signaling Pathways
Authors: Thomas Force, Keisuke Kuida, Mark Namchuk, Keykavous Parang, John M. Kyriakis
Journal: Circulation (2004)

Protein kinases are enzymes that covalently modify proteins by attaching phosphate groups (from ATP) to serine, threonine, and/or tyrosine residues. In so doing, the functional properties of the protein kinase's substrates are modified. Protein kinases transduce signals from the cell membrane into the interior of the cell. Such signals include not only those arising from ligand-receptor interactions but also environmental perturbations such as when the membrane undergoes mechanical deformation (ie, cell stretch or shear stress). Ultimately, the activation of signaling pathways that use protein kinases often culminates in the reprogramming of gene expression through the direct regulation of transcription factors or through the regulation of mRNA stability or protein translation. Protein kinases regulate most aspects of normal cellular function. The pathophysiological dysfunction of protein kinase signaling pathways underlies the molecular basis of many cancers and of several manifestations of cardiovascular disease, such as hypertrophy and other types of left ventricular remodeling, ischemia/reperfusion injury, angiogenesis, and atherogenesis. Given their roles in such a wide variety of disease states, protein kinases are rapidly becoming extremely attractive targets for drug discovery, probably second only to heterotrimeric G protein-coupled receptors (eg, angiotensin II). Here, we will review the reasons for this explosion in interest in inhibitors of protein kinases and will describe the process of identifying novel drugs directed against kinases. We will specifically focus on disease states for which drug development has proceeded to the point of clinical or advanced preclinical studies.
Spontaneous Spinal Cerebrospinal Fluid Leaks and Intracranial Hypotension
Authors: Wouter I Schievink
Journal: JAMA (2006)

ContextSpontaneous intracranial hypotension is caused by spontaneous spinal cerebrospinal fluid (CSF) leaks and is known for causing orthostatic headaches. It is an important cause of new headaches in young and middle-aged individuals, but initial misdiagnosis is common.ObjectiveTo summarize existing evidence regarding the epidemiology, pathophysiology, diagnosis, and management of spontaneous spinal CSF leaks and intracranial hypotension.Evidence AcquisitionMEDLINE (1966-2005) and OLDMEDLINE (1950-1965) were searched using the terms intracranial hypotension, CSF leak, low pressure headache, and CSF hypovolemia. Reference lists of these articles and ongoing investigations in this area were used as well.Evidence SynthesisSpontaneous intracranial hypotension is caused by single or multiple spinal CSF leaks. The incidence has been estimated at 5 per 100 000 per year, with a peak around age 40 years. Women are affected more commonly than men. Mechanical factors combine with an underlying connective tissue disorder to cause the CSF leaks. An orthostatic headache is the prototypical manifestation but other headache patterns occur as well, and associated symptoms are common. Typical magnetic resonance imaging findings include subdural fluid collections, enhancement of the pachymeninges, engorgement of venous structures, pituitary hyperemia, and sagging of the brain (mnemonic: SEEPS). Myelography is the study of choice to identify the spinal CSF leak. Treatments include bed rest, epidural blood patching, percutaneous placement of fibrin sealant, and surgical CSF leak repair, but outcomes have been poorly studied and no management strategies have been studied in properly controlled randomized trials.ConclusionsSpontaneous intracranial hypotension is not rare but it remains underdiagnosed. The spectrum of clinical and radiographic manifestations is varied, with diagnosis largely based on clinical suspicion, cranial magnetic resonance imaging, and myelography. Numerous treatment options are available, but much remains to be learned about this disorder.
Comparison of Murine Nasal-associated Lymphoid Tissue and Peyer's Patches
Authors: PHILIPPA L. HERITAGE, BRIAN J. UNDERDOWN, A. LARRY ARSENAULT, DENIS P. SNIDER, MARK R. McDERMOTT
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

The nasal mucosal is the first site of contact with inhaled antigens. However, the nature of local immune responses and the role of nasal-associated lymphoid tissue (NALT) in those responses have rarely been studied. To characterize the cells involved in mucosally derived immune responses, NALT and Peyer's patch (PP) cells from normal mice, and mice immunized intragastrically or intranasally with cholera toxin (CT), were isolated and analyzed. Compared with PP cells, unstimulated NALT cells contained a higher proportion of T-cells. The CD4:CD8 ratio in NALT cell preparations was less than that observed in PP and more closely resembled that seen in spleen. Additionally, the total B-cell frequency in NALT cell isolates was 20% lower than that observed in PP cell preparations. Although NALT and PP cell isolates contained both mature B-cells and cells undergoing activation to express surface IgA, unlike PP, NALT showed no significant frequency of IgA-switched cells. After intranasal immunization with CT, toxin-specific IgA antibody-forming cells (AFCs) were detected in NALT cell preparations. The numbers of these cells correlated with CT-specific IgA in nasal, but not in gut washes or sera, thus suggesting local nasal production of antigen-specific mucosal antibodies. There was no evidence of anti-CT AFCs in NALT or CT-specific antibody in nasal washes after intragastric CT administration. These results support the notion that nasal mucosal antibody production is best achieved via direct stimulation of IgA-committed, NALT-derived B-cells.
A Phase I Study of Continuous Oral Dosing of OSI-906, a Dual Inhibitor of Insulin-Like Growth Factor-1 and Insulin Receptors, in Patients with Advanced Solid Tumors
Authors: Igor Puzanov, Colin R. Lindsay, Laura Goff, Jeff Sosman, Jill Gilbert, Jordan Berlin, Srinivasu Poondru, Ronit Simantov, Rich Gedrich, Andrew Stephens, Emily Chan, T.R. Jeffry Evans
Journal: Clinical Cancer Research (2014)

Abstract Purpose: OSI-906 is a potent inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR). The purpose of this study was to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906 in patients with advanced solid tumors. Patients and Methods: This was a nonrandomized, open-label, phase I, dose-escalation study in patients with advanced solid tumors. The study also included a diabetic expansion cohort and a biomarker expansion cohort of patients with colorectal cancer. Patients were treated with OSI-906 by once- or twice-daily continuous dosing schedules. Results: Of 95 patients enrolled in the study, 86 received at least one dose of OSI-906. Dose-limiting toxicities included QTc prolongation, grade 2 abdominal pain and nausea, hyperglycemia, and elevation of aspartate aminotransferase and alanine aminotransferase (all grade 3). The MTDs were established to be 400 mg once daily and 150 mg twice daily. The recommended phase II dose was determined as 150 mg twice daily. OSI-906 was rapidly absorbed with a half-life of 5 hours, and steady-state plasma concentrations were achieved by day 8. Pharmacodynamic effects on IGF1R and IR phosphorylation were levels observed and correlated with plasma concentrations of OSI-906. Thirty-one patients had stable disease as their best response. One patient with melanoma had a radiographic partial response and underwent resection, during which only melanocytic debris but no viable tumor tissue was identified. Conclusions: At the established MTD, OSI-906 was well tolerated and antitumor activity was observed. These results support further evaluation of OSI-906 in solid tumors. Clin Cancer Res; 21(4); 701–11. ©2014 AACR. See related commentary by Yee, p. 667
Regular salbutamol use increases CXCL8 responses in asthma: relationship to the eosinophil response
Authors: J.R. Gordon, V.A. Swystun, F. Li, X. Zhang, B.E. Davis, P. Hull, D.W. Cockcroft
Journal: European Respiratory Journal (2003)

Regular salbutamol use can exacerbate allergen-induced airway eosinophilia in asthmatics, but its effect on airway eosinophil chemokine responses is unknown. Asthmatic subjects (n=14) were treated for 10 days with placebo or salbutamol in a double-blind, cross-over study, then given same-dose allergen challenges. Their sputa were then analysed 1 and 7 h later for a panel of eosinophil-related cytokines. Eosinophils from five test and three control subjects were tested for expression of CXCL8/interleukin (IL)‐8, and its receptors and responsiveness to CCL11/eotaxin and CXCL8/IL‐8. Sputum CXCL8/IL‐8, but not IL‐5, CCL5/regulated on activation, T‐cell expressed and secreted, CCL7/monocyte chemotactic protein‐3, CCL11/eotaxin, granulocyte-macrophage colony-stimulating factor or tumour necrosis factor levels, were increased (42%) by the salbutamol treatments. The CXCL8/IL‐8 levels correlated with the proportions of sputum eosinophils and these cells, but not other sputum cells, stained strongly for CXCL8/IL‐8. The circulating eosinophils of the tested subjects (n=5) expressed CXCL8/IL‐8 receptors and secreted high levels of this chemokine. Neutralisation of sputum CXCL8/IL‐8 reduced eosinophil chemotactic responses to these samples by 19±5%. These data suggest that regular use of salbutamol can augment airway CXCL8/interleukin‐8 responses to allergen challenge and that this CXCL8/interleukin‐8 could contribute to the airway inflammatory response.
NAC Protects Against Benzyl Isothiocyanate Induced G2/M Arrest and Apoptosis in Human Pancreatic Cancer Cells.
Authors: Ruifen Zhang, Sanjay K. Srivastava
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

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Previously, we showed that benzyl isothiocyanate (BITC), a naturally occurring anti-cancer agent present in cruciferous vegetables, inhibits the proliferation of Capan-2 human pancreatic cancer cells by causing cell cycle arrest and apoptosis. However, the exact mechanisms of growth suppressive effects of BITC were not clear. Here we demonstrate that BITC treatment of Capan-2 cells resulted in the significantly increased expression of cyclin dependent kinase (cdk) inhibitor p21 in a dose-dependent manner concomitant with decreased expression of cdk1. Treatment of these cells with growth suppressive concentration of BITC for 24h resulted in significant accumulation of cells in G2/M phase and induction of apoptosis as measured by flow cytometery. Interestingly, pretreatment of cells with N-acetyl cysteine (NAC), a common antioxidant, significantly protected Capan-2 cells from BITC-induced G2/M arrest as well as apoptosis. NAC treatment also prevented BITC-mediated up regulation of the expression of p21, suggesting the involvement of reactive oxygen species (ROS). We next demonstrated that BITC-treatment causes significant generation of ROS, as measured by DCF fluorescence and that NAC almost completely blocked the generation of BITC-mediated ROS. We therefore, conclude that generation of ROS may be the key factor in BITC-mediated increased p21 expression, which in turn may be responsible for G2/M arrest and apoptosis in these cells. [Supported in part by RO1 grant CA 106953 (to S.K.S.) awarded by the National Cancer Institute].
A novel mechanism for MET and EGFR axis regulation in non-small cell lung cancer involving microRNA-27a and Sprouty2
Authors: Omair Shariq
Journal: Thorax (2013)

Epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (MET) are tyrosine kinase receptors that have been implicated in the pathogenesis of non-small cell lung cancer (NSLC). Sprouty2, a ubiquitously expressed protein, has been shown to upregulate EGFR and MET in several types of cancers. Conversely, microRNAs are small non-coding RNA molecules that regulate gene expression negatively, and microRNA-27a (miR-27a) …