tbuckley/cabot-search huggingface dataset:
cAMP-Dependent Vasodilators Cross-Activate the cGMP-Dependent Protein Kinase to Stimulate BK <sub>Ca</sub> Channel Activity in Coronary Artery Smooth Muscle Cells
Authors: Richard E. White, Jonathan P. Kryman, Abdalla M. El-Mowafy, Guichun Han, Gerald O. Carrier
Journal: Circulation Research (2000)

Abstract —cAMP-dependent vasodilators are used to treat a variety of cardiovascular disorders; however, the signal transduction pathways and effector mechanisms stimulated by these agents are not fully understood. In the present study we demonstrate that cAMP-stimulating agents enhance the activity of the large-conductance, calcium-activated potassium (BK Ca ) channel in single myocytes from coronary arteries by “cross-activation” of the cGMP-dependent protein kinase (protein kinase G, PKG). Single-channel patch-clamp data revealed that 10 μmol/L isoproterenol, forskolin, or dopamine opens BK Ca channels in coronary myocytes and that this effect is attenuated by inhibitors of PKG (KT5823; Rp-8-pCPT-cGMPS), but not by inhibiting the cAMP-dependent protein kinase (protein kinase A, PKA). In addition, a membrane-permeable analog, CPT-cAMP, also opened BK Ca channels in these myocytes, and this effect was reversed by KT5823. Direct biochemical measurement confirmed that dopamine or forskolin stimulates PKG activity in coronary arteries but does not elevate cGMP. Finally, the stimulatory effect of cAMP on BK Ca channels was reconstituted in a cell-free, inside-out patch by addition of purified PKG activated by either cGMP or cAMP. In contrast, channel gating was unaffected by exposure to the purified catalytic subunit of PKA. In summary, findings from on-cell and cell-free patch-clamp experiments provide direct evidence that cAMP-dependent vasodilators open BK Ca channels in coronary myocytes by cross-activation of PKG (but not via PKA). Biochemical assay confirmed this cross-activation mechanism of cAMP action in these arteries. This signaling pathway is a novel mechanism for regulation of potassium channel activity in vascular smooth muscle and other cells.
Phase 1 Study of Weekly Polyethylene Glycol-Camptothecin in Patients with Advanced Solid Tumors and Lymphomas
Authors: James A. Posey, M. Wasif Saif, Ronda Carlisle, Andrew Goetz, Jinee Rizzo, Suzanne Stevenson, Marc S. Rudoltz, Joseph Kwiatek, Paul Simmons, Eric K. Rowinsky, Chris H. Takimoto, Anthony W. Tolcher
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To determine the maximal tolerated dose and dose-limiting toxicities (DLT) of pegamotecan (polyethylene glycol-camptothecin) in patients with advanced malignancies when administered in cycles of once weekly for 3 of 4 weeks. Experimental Design: Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, including also the following criteria: measurable disease, Eastern Cooperative Oncology Group performance status of ≤2, and acceptable organ function. Pegamotecan was administered as a 60-minute infusion, with successive patient cohorts receiving escalating doses from 800 to 4,300 mg/m2. The primary end point was to determine the maximal tolerated dose. Other end points were toxicity, pharmacokinetics, pharmacodynamics, and efficacy. Pharmacokinetic analysis measured free camptothecin. Pharmacodynamic analysis correlated drug effects with pegamotecan dose and pharmacokinetic variables. Results: Twenty-seven patients were enrolled. The maximal tolerated dose was 3,240 mg/m2. Grade 4 neutropenia, the DLT, was noted in two of four patients treated at 4,300 mg/m2. Other grade 3 and 4 toxicities were anemia, thrombocytopenia, fatigue, prolonged partial thromboplastin time, hemorrhagic cystitis, dysuria, and urinary frequency. Pharmacokinetic analysis showed the apparent terminal elimination half-life to be 46 ± 12.8 hours. Pharmacodynamic analysis showed that hematuria occurred in 8 of 15 patients with an area under the curve extrapolated to infinity (AUC0-∞) &amp;gt; 20 ng h/mL and 0 of 10 patients with an AUC0-∞ ≤ 20 ng h/mL. Unconfirmed partial responses were observed in two patients, one with metastatic small bowel adenocarcinoma and the other with metastatic esophageal cancer. Conclusions: The maximal tolerated dose of pegamotecan when administered weekly for 3 of 4 weeks is 3,240 mg/m2. The DLT was neutropenia. Among nonhematologic toxicities, the incidence of gastrointestinal toxicity was low, but genitourinary toxicity seems to occur in the same effective dose range as noted with native camptothecin in earlier trials (27-43 mg/m2). The observed antitumor activity suggests that pegamotecan has single-agent activity and merits further investigation in phase 2 studies.
Sport injuries and illnesses during the first Winter Youth Olympic Games 2012 in Innsbruck, Austria
Authors: Gerhard Ruedl, Wolfgang Schobersberger, Elena Pocecco, Cornelia Blank, Lars Engebretsen, Torbjørn Soligard, Kathrin Steffen, Martin Kopp, Martin Burtscher
Journal: British Journal of Sports Medicine (2012)

Background Data on the injury and illness risk among young elite athletes are of utmost importance, because injuries and illnesses can counter the beneficial effects of sports participation at a young age, if children or adolescents are unable to continue to participate because of residual effects of injury or chronic illness. Objective To analyse the frequencies and characteristics of injuries and illnesses during the 2012 Innsbruck Winter Youth Olympic Games (IYOG). Methods We employed the International Olympic Committee (IOC) injury surveillance system for multisport events, which was updated for the Winter Olympic Games in Vancouver 2010. All National Olympic Committees (NOCs) were asked to report the daily occurrence (or non-occurrence) of newly sustained injuries and illnesses on a standardised reporting form. In addition, information on athletes treated for injuries and illnesses by the Local Organizing Committee medical services was retrieved from the medical centre at the Youth Olympic Village and from the University hospital in Innsbruck. Results Among the 1021 registered athletes (45% women, 55% men) from 69 NOCs, a total of 111 injuries and 86 illnesses, during the IYOG, were reported, resulting in an incidence of 108.7 injuries and 84.2 illnesses per 1000 registered athletes, respectively. Injury frequency was highest in skiing in the halfpipe (44%) and snowboarding (halfpipe and slope style: 35%), followed by ski cross (17%), ice hockey (15%), alpine skiing (14%) and figure skating (12%), taking into account the respective number of participating athletes. Knee, pelvis, head, lower back and shoulders were the most common injury locations. About 60% of injuries occurred in competition and about 40% in training, respectively. In total, 32% of the injuries resulted in an absence from training or competition. With regard to illnesses, 11% of women and 6% of men suffered from an illness (RR=1.84 (95% CI 1.21 to 2.78), p=0.003). The respiratory system was affected most often (61%). Conclusions Eleven per cent of the athletes suffered from an injury and 9% from illnesses, during the IYOG. The presented data constitute the basis for future analyses of injury mechanisms and associated risk factors in Olympic Winter sports, which, in turn, will be essential to develop and implement effective preventive strategies for young elite winter-sport athletes.
NQO1 Suppresses NF-κB–p300 Interaction to Regulate Inflammatory Mediators Associated with Prostate Tumorigenesis
Authors: Dinesh Thapa, Peng Meng, Roble G. Bedolla, Robert L. Reddick, Addanki P. Kumar, Rita Ghosh
Journal: Cancer Research (2014)

NADPH reductasequinone oxidoreductase 1 (NQO1) is needed to maintain a cellular pool of antioxidants, and this enzyme may contribute to tumorigenesis on the basis of studies in NQO1-deficient mice. In this work, we sought deeper insights into how NQO1 contributes to prostate carcinogenesis, a setting in which oxidative stress and inflammation are established contributors to disease development and progression. In the TRAMP mouse model of prostate cancer, NQO1 was highly expressed in tumor cells. NQO1 silencing in prostate cancer cells increased levels of nuclear IKKα and NF-κB while decreasing the levels of p53, leading to interactions between NF-κB and p300 that reinforce survival signaling. Gene expression analysis revealed upregulation of a set of immune-associated transcripts associated with inflammation and tumorigenesis in cells in which NQO1 was attenuated, with IL8 confirmed functionally in cell culture as one key NQO1-supported cytokine. Notably, NQO1-silenced prostate cancer cells were more resistant to androgen deprivation. Furthermore, NQO1 inhibition increased migration, including under conditions of androgen deprivation. These results reveal a molecular link between NQO1 expression and proinflammatory cytokine signaling in prostate cancer. Furthermore, our results suggest that altering redox homeostasis through NQO1 inhibition might promote androgen-independent cell survival via opposing effects on NF-κB and p53 function.
Effect of Long-Chain ω-3 Fatty Acids and Lutein + Zeaxanthin Supplements on Cardiovascular Outcomes
Authors: Denise E. Bonds, Molly Harrington, Bradford B. Worrall, Alain G. Bertoni, Charles B. Eaton, Judy Hsia, Jennifer Robinson, Traci E. Clemons, Lawrence J. Fine, Emily Y. Chew
Journal: JAMA Internal Medicine (2014)

Dietary supplements have been proposed as a mechanism to improve health and prevent disease.To determine if supplementing diet with long-chain ω-3 polyunsaturated fatty acids or with macular xanthophylls results in a reduced rate of cardiovascular disease (CVD).The Cardiovascular Outcome Study (COS) was an ancillary study of the Age-Related Eye Disease Study 2 (AREDS2), a factorial-designed randomized clinical trial of 4203 participants recruited from 82 US academic and community ophthalmology clinics, who were followed up for a median of 4.8 years. Individuals were eligible to participate if they were between the ages of 50 and 85 years, had intermediate or advanced age-related macular degeneration in 1 eye, and were willing to be randomized. Participants with stable, existing CVD (>12 months since initial event) were eligible to participate. Participants, staff, and outcome assessors were masked to intervention.Daily supplementation with long-chain ω-3 polyunsaturated fatty acids (350-mg docosahexaenoic acid [DHA] + 650-mg eicosapentaenoic acid [EPA]), macular xanthophylls (10-mg lutein + 2-mg zeaxanthin), combination of the two, or matching placebos. These treatments were added to background therapy of the AREDS vitamin and mineral formulation for macular degeneration. MAIN OUTCOMES AND MEASURES A composite outcome of myocardial infarction, stroke, and cardiovascular death with 4 prespecified secondary combinations of the primary outcome with hospitalized heart failure, revascularization, or unstable angina.Study participants were primarily white, married, and highly educated, with a median age at baseline of 74 years. A total of 602 cardiovascular events were adjudicated, and 459 were found to meet 1 of the study definitions for a CVD outcome. In intention-to-treat analysis, no reduction in the risk of CVD or secondary CVD outcomes was seen for the DHA + EPA (primary outcome: hazard ratio [HR], 0.95; 95% CI, 0.78-1.17) or lutein + zeaxanthin (primary outcome: HR, 0.94; 95% CI, 0.77-1.15) groups. No differences in adverse events or serious adverse event were seen by treatment group. The sample size was sufficient to detect a 25% reduction in CVD events with 80% power.Dietary supplementation of long-chain ω-3 polyunsaturated fatty acids or macular xanthophylls in addition to daily intake of minerals and vitamins did not reduce the risk of CVD in elderly participants with age-related macular degeneration.clinicaltrials.gov Identifier: NCT00345176.
Anterior Cingulate Gyrus Dysfunction and Selective Attention Deficits in Schizophrenia: [<sup>15</sup>O]H<sub>2</sub>O PET Study During Single-Trial Stroop Task Performance
Authors: Cameron S. Carter, Mark Mintun, Thomas Nichols, Jonathan D. Cohen
Journal: American Journal of Psychiatry (1997)

OBJECTIVE: Attentional deficits are a prominent aspect of cognitive dysfunction in schizophrenia. The anterior cingulate gyrus is proposed to be an important component of frontal attentional control systems. Structural and functional abnormalities have been reported in this region in schizophrenia, but their relationship to attentional deficits is unknown. The authors investigated the function of the anterior cingulate gyrus and the related neural systems that are associated with selective attention in patients with schizophrenia. METHOD: While subjects performed multiple blocks of a single-trial Stroop task, [15O]H2O positron emission tomography scans were obtained. Fourteen patients with schizophrenia were compared with 15 normal subjects matched for age, gender, and parental education. RESULTS: The patients with schizophrenia responded at the same rate but made more errors in color naming during the color-incongruent condition. Consistent with the authors' hypothesis, patients with schizophrenia showed significantly less anterior cingulate gyrus activation while naming the color of color-incongruent stimuli. CONCLUSIONS: Patients with schizophrenia fail to activate the anterior cingulate gyrus during selective attention performance. This finding adds to the understanding of the functional significance of the structural and metabolic abnormalities in schizophrenia that have been previously reported in this region of the brain. (Am J Psychiatry 1997; 154:1670–1675)
The D0 Domain of KIR3D Acts as a Major Histocompatibility Complex Class I Binding Enhancer
Authors: Salim I. Khakoo, Ron Geller, Sunny Shin, Jomaquai A. Jenkins, Peter Parham
Journal: The Journal of Experimental Medicine (2002)

In contrast to the KIR2D:HLA-C interaction, little is known of KIR3DL1's interaction with HLA-B or the role of D0, the domain not present in KIR2D. Differences in the strength and specificity for major histocompatibility complex class I of KIR3DL1 and its common chimpanzee homologue Pt-KIR3DL1/2 were exploited to address these questions. Domain-swap, deletion, and site-directed mutants of KIR3DL1 were analyzed for HLA-B binding using a novel, positively signaling cell–cell binding assay. Natural ‘deletion’ of residues 50 and 51 from its D0 domain causes Pt-KIR3DL1/2 to bind Bw4+ HLA-B allotypes more avidly than does KIR3DL1. Deletion of these residues from KIR3DL1, or their substitution for alanine, enhanced binding of Bw4+ HLA-B. None of 15 different point mutations in D0 abrogated KIR3DL1 binding to Bw4+ HLA-B. In contrast point mutations in the D1 and D2 domains of KIR3DL1, made from knowledge of KIR2D:HLA-C interactions, disrupted binding to Bw4+ HLA-B. The results are consistent with a model in which D1 and D2 make the principal contacts between KIR3DL1 and HLA-B while D0 acts through a different mechanism to enhance the interaction. This modulatory role for D0 is compatible with natural loss of expression of the D0 domain, a repeated event in the evolution of functional KIR genes.
Suberoylanilide Hydroxamic Acid, a Histone Deacetylase Inhibitor: Effects on Gene Expression and Growth of Glioma Cells <i>In vitro</i> and <i>In vivo</i>
Authors: Dong Yin, John M. Ong, Jinwei Hu, Julian C. Desmond, Norihiko Kawamata, Bindu M. Konda, Keith L. Black, H. Phillip Koeffler
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Histone acetylation is one of the main mechanisms involved in regulation of gene expression. During carcinogenesis, tumor-suppressor genes can be silenced by aberrant histone deacetylation. This epigenetic modification has become an important target for tumor therapy. The histone deacetylation inhibitor, suberoylanilide hydroxamic acid (SAHA), can induce growth arrest in transformed cells. The aim of this study is to examine the effects of SAHA on gene expression and growth of glioblastoma multiforme (GBM) cells in vitro and in vivo. Experimental Design: The effect of SAHA on growth of GBM cell lines and explants was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Changes of the cell cycle and relative gene expression were detected by fluorescence-activated cell sorting, real-time reverse transcription-PCR, and Western blotting. After glioma cells were implanted in the brains of mice, the ability of SAHA to decrease tumor growth was studied. Results: Proliferation of GBM cell lines and explants were inhibited in vitro by SAHA (ED50, 2 × 10−6 to 2 × 10−5 mol/L, 5 days). SAHA exposure of human U87 and T98G glioma cell lines, DA66 and JM94 GBM explants, as well as a murine GL26 GBM cell line resulted in an increased accumulation of cells in G2-M of the cell cycle. Many proapoptotic, antiproliferative genes increased in their expression (DR5, TNFα, p21WAF1, p27KIP1), and many antiapoptotic, progrowth genes decreased in their levels (CDK2, CDK4, cyclin D1, cyclin D2) as measured by real-time reverse transcription-PCR and/or Western blot after these GBM cells were cultured with SAHA (2.5 × 10−6 mol/L, 1 day). Chromatin immunoprecipitation assay found that acetylation of histone 3 on the p21WAF1 promoter was markedly increased by SAHA. In vivo murine experiments suggested that SAHA (10 mg/kg, i.v., or 100 mg/kg, i.p.) could cross the blood-brain barrier as shown by prominent increased levels of acetyl-H3 and acetyl-H4 in the brain tissue. Furthermore, the drug significantly (P &amp;lt; 0.05) inhibited the proliferation of the GL26 glioma cells growing in the brains of mice and increased their survival. Conclusions: Taken together, SAHA can slow the growth of GBM in vitro and intracranially in vivo. SAHA may be a welcome addition for the treatment of this devastating disease.
A universal approach to modeling visual word recognition and reading: Not only possible, but also inevitable
Authors: Ram Frost
Journal: Behavioral and Brain Sciences (2012)

Abstract I have argued that orthographic processing cannot be understood and modeled without considering the manner in which orthographic structure represents phonological, semantic, and morphological information in a given writing system. A reading theory, therefore, must be a theory of the interaction of the reader with his/her linguistic environment. This outlines a novel approach to studying and modeling visual word recognition, an approach that focuses on the common cognitive principles involved in processing printed words across different writing systems. These claims were challenged by several commentaries that contested the merits of my general theoretical agenda, the relevance of the evolution of writing systems, and the plausibility of finding commonalities in reading across orthographies. Other commentaries extended the scope of the debate by bringing into the discussion additional perspectives. My response addresses all these issues. By considering the constraints of neurobiology on modeling reading, developmental data, and a large scope of cross-linguistic evidence, I argue that front-end implementations of orthographic processing that do not stem from a comprehensive theory of the complex information conveyed by writing systems do not present a viable approach for understanding reading. The common principles by which writing systems have evolved to represent orthographic, phonological, and semantic information in a language reveal the critical distributional characteristics of orthographic structure that govern reading behavior. Models of reading should thus be learning models, primarily constrained by cross-linguistic developmental evidence that describes how the statistical properties of writing systems shape the characteristics of orthographic processing. When this approach is adopted, a universal model of reading is possible.
Gene expression dynamics after murine pancreatitis unveils novel roles for Hnf1α in acinar cell homeostasis
Authors: Xavier Molero, Eva Cristina Vaquero, Marta Flández, Ana María González, Maria Ángels Ortiz, Elena Cibrián-Uhalte, Joan-Marc Servitja, Anna Merlos, Núria Juanpere, Mohammad Massumi, Anouchka Skoudy, Raymond MacDonald, Jorge Ferrer, Francisco X Real
Journal: Gut (2011)

<h3>Objectives</h3> During pancreatitis, specific transcriptional programmes govern functional regeneration after injury. The objective of this study was to analyse the dynamic regulation of pancreatic genes and the role of transcriptional regulators during recovery from pancreatitis. <h3>Design</h3> Wild-type and genetically modified mice (Hnf1α<sup>−/−</sup> and Ptf1a<sup>+/−</sup>) were used. After caerulein or l-arginine induced pancreatitis, blood or pancreata were processed for enzymatic assays, ELISA, histology, immunohistochemistry, western blotting and quantitative reverse transcriptase-PCR. <i>Nr5a2</i> promoter reporter and chromatin immunoprecipitation assays for Hnf1α were also performed. <h3>Results</h3> After caerulein pancreatic injury, expression of acinar and endocrine genes rapidly decreased, but eventually recovered, depicting distinct cell-type-specific patterns. Pdx1 and Hnf1α mRNAs underwent marked downregulation, matching endocrine/exocrine gene expression profiles. Ptf1a, Pdx1 and Hnf1α protein levels were also reduced and recovered gradually. These changes were associated with transient impairment of exocrine and endocrine function, including abnormal glucose tolerance. On l-arginine pancreatitis, changes in Ptf1a, Pdx1 and Hnf1α gene and protein expression were recapitulated. Reduced Hnf1α and Ptf1a levels after pancreatitis coincided with increased acinar cell proliferation, both in Hnf1α<sup>−/−</sup> and Ptf1a<sup>+/−</sup> mice. Moreover, Hnf1α<sup>−/−</sup> mice had reduced Ptf1a protein as well as transcripts for Ptf1a and digestive enzymes. Dispersed acini from Hnf1α<sup>−/−</sup> mice showed suboptimal secretory responses to caerulein. Bioinformatics analysis did not support a role for Hnf1α as a direct regulator of digestive enzyme genes. Instead, it was found that Hnf1α binds to, and regulates, the promoter of <i>Nr5a2</i>, coding an orphan nuclear receptor that regulates acinar gene expression. <h3>Conclusions</h3> Dynamic changes in gene expression occur on pancreatitis induction, determining altered exocrine and endocrine function. This analysis uncovers roles for Hnf1α in the regulation of acinar cell determination and function. This effect may be mediated, in part, through direct regulation of <i>Nr5a2</i>.