tbuckley/cabot-search huggingface dataset:
Effect of Endogenous and Exogenous Prostaglandin E<sub>2</sub>on Interleukin-1 β –Induced Cyclooxygenase-2 Expression in Human Airway Smooth-Muscle Cells
Authors: ALBINO BONAZZI, MANLIO BOLLA, CAROLA BUCCELLATI, ALICIA HERNANDEZ, SIMONA ZARINI, TERESA VIGANÒ, FRANCESCA FUMAGALLI, SERENA VIAPPIANI, SAULA RAVASI, PIERO ZANNINI, GIUSEPPE CHIESA, GIANCARLO FOLCO, ANGELO SALA
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

We studied the effect of endogenous and exogenous prostaglandin E2 (PGE2), a metabolite of arachidonic acid through the cyclooxygenase (COX) pathway, on interleukin (IL)-1 β –induced COX-2 expression, using primary cultures of human bronchial smooth-muscle cells (HBSMC). Treatment with exogenous PGE2 resulted in enhanced expression of IL-1 β –induced COX-2 protein and messenger RNA (mRNA) as compared with the effect of the cytokine per se. Inhibition of PGE2 production with a nonselective COX inhibitor (flurbiprofen, 10 μ M) resulted in a significant reduction in IL-1 β – induced COX-2 expression, supporting a role of endogenous COX metabolites in the modulation of COX-2 expression. None of the experimental conditions used in the study affected the expression of constitutive cyclooxygenase (COX-1). Treatment with cycloheximide to inhibit translation, and with dexamethasone or actinomycin D to inhibit transcription, linked the effect of PGE2 to the transcriptional level of COX-2 mRNA rather than to a potential effect on protein and/or mRNA stabilization. PGE2 increased adenylate cyclase activity in a concentration dependent manner, and forskolin, a direct activator of adenylate cyclase, caused a marked increase in IL-1 β –dependent COX-2, suggesting the existence of a causal relationship between the two events. The same results were observed with salbutamol, a bronchodilator that acts by increasing cyclic adenosine monophosphate. The effect of PGE2 on COX-2 expression may contribute to the hypothesized antiinflammatory role of PGE2 in human airways, providing a self-amplifying loop leading to increased biosynthesis of PGE2 during an inflammatory event.
Secular Trends in Incidence of Atrial Fibrillation in Olmsted County, Minnesota, 1980 to 2000, and Implications on the Projections for Future Prevalence
Authors: Yoko Miyasaka, Marion E. Barnes, Bernard J. Gersh, Stephen S. Cha, Kent R. Bailey, Walter P. Abhayaratna, James B. Seward, Teresa S.M. Tsang
Journal: Circulation (2006)

Background— Limited data exist on trends in incidence of atrial fibrillation (AF). We assessed the community-based trends in AF incidence for 1980 to 2000 and provided prevalence projections to 2050. Methods and Results— The adult residents of Olmsted County, Minnesota, who had ECG-confirmed first AF in the period 1980 to 2000 (n=4618) were identified. Trends in age-adjusted incidence were determined and used to construct model-based prevalence estimates. The age- and sex-adjusted incidence of AF per 1000 person-years was 3.04 (95% CI, 2.78 to 3.31) in 1980 and 3.68 (95% CI, 3.42 to 3.95) in 2000. According to Poisson regression with adjustment for age and sex, incidence of AF increased significantly ( P =0.014), with a relative increase of 12.6% (95% CI, 2.1 to 23.1) over 21 years. The increase in age-adjusted AF incidence did not differ between men and women ( P =0.84). According to the US population projections by the US Census Bureau, the number of persons with AF is projected to be 12.1 million by 2050, assuming no further increase in age-adjusted incidence of AF, but 15.9 million if the increase in incidence continues. Conclusions— The age-adjusted incidence of AF increased significantly in Olmsted County during 1980 to 2000. Whether or not this rate of increase continues, the projected number of persons with AF for the United States will exceed 10 million by 2050, underscoring the urgent need for primary prevention strategies against AF development.
The<i>Caenorhabditis elegans</i>Dopaminergic System: Opportunities for Insights into Dopamine Transport and Neurodegeneration
Authors: Richard Nass, Randy D. Blakely
Journal: The Annual Review of Pharmacology and Toxicology (2003)

The neurotransmitter dopamine (DA) plays a central role in the coordination of movement, attention, and the recognition of reward. Loss of DA from the basal ganglia, as a consequence of degeneration of neurons in the substantia nigra, triggers postural instability and Parkinson's disease (PD). DA transporters (DATs) regulate synaptic DA availability and provide a conduit for the uptake of DA mimetic neurotoxins, which can be used to evoke neuronal death and Parkinson-like syndrome. Recently, we have explored the sensitivity of DA neurons in the nematode Caenorhabditis elegans to the Parkinsonian-inducing neurotoxin 6-hydroxydopamine (6-OHDA) and found striking similarities, including DAT dependence, to neurodegeneration observed in mammalian models. In this review, we present our findings in the context of molecular and behavioral dimensions of DA signaling in C. elegans with an eye toward opportunities for uncovering DAT mutants, DAT regulators, and components of toxin-mediated cell death.
Specific TP53 and/or Ki-ras mutations as independent predictors of clinical outcome in sporadic colorectal adenocarcinomas: results of a 5-year Gruppo Oncologico dell'Italia Meridionale (GOIM) prospective study
Authors: V. Bazan, V. Agnese, S. Corsale, V. Calò, M.R. Valerio, M.A. Latteri, S. Vieni, N. Grassi, G. Cicero, G. Dardanoni, R.M. Tomasino, G. Colucci, N. Gebbia, A. Russo
Journal: Annals of Oncology (2005)
Mechanisms of Light Chain Injury along the Tubular Nephron
Authors: Paul W. Sanders
Journal: Journal of the American Society of Nephrology (2012)

The tubular nephron is responsible for reabsorption and catabolism of filtered low molecular weight proteins that include Ig free light chains. In the setting of a plasma cell dyscrasia, significant amounts of free light chains, now monoclonal proteins, present to the tubular nephron for disposal. The result may be clinical renal dysfunction in the form of AKI, progressive CKD, and end-stage kidney disease. Here, I review the mechanisms involved in these processes that result in tubular injury, including proximal tubulopathy and cast nephropathy.
“Gamma Synchrony” in First-Episode Schizophrenia: A Disorder of Temporal Connectivity?
Authors: Matthew B. Symond, Anthony W.F. Harris, Evian Gordon, Leanne M. Williams
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: There has been a convergence of models describing schizophrenia as a disconnection syndrome, with a focus on the temporal connectivity of neural activity. Synchronous gamma-band (40-Hz) activity has been implicated as a candidate mechanism for the binding of distributed neural activity. To the authors’ knowledge, this is the first study to investigate “gamma synchrony” in first-episode schizophrenia. METHOD: Forty medicated first-episode schizophrenia patients and 40 age- and sex-matched healthy comparison subjects participated in a conventional auditory oddball paradigm. Gamma synchrony, time-locked to target stimuli, was extracted from an ongoing EEG. The magnitude and latency of both early (gamma 1: –150 msec to 150 msec poststimulus) and late (gamma 2: 200 to 550 msec poststimulus) synchrony were analyzed with multiple analysis of variance. RESULTS: First-episode schizophrenia patients showed a decreased magnitude and delayed latency for global gamma 1 synchrony in relation to healthy comparison subjects. By contrast, there were no group differences in gamma 2 synchrony. CONCLUSIONS: These findings suggest that first-episode schizophrenia patients have a global decrease and delay of temporal connectivity of neural activity in early sensory response to task-relevant stimuli. This is consistent with cognitive evidence of perceptual integration deficits in this disorder and raises the possibility that a breakdown in the early synchrony of distributed neural networks is a marker for the onset of schizophrenia.
Prognostic Implications of Cell Cycle, Apoptosis, and Angiogenesis Biomarkers in Non–Small Cell Lung Cancer: A Review
Authors: Sunil Singhal, Anil Vachani, Danielle Antin-Ozerkis, Larry R. Kaiser, Steven M. Albelda
Journal: Clinical Cancer Research (2005)

Abstract Lung cancer is the leading cause of cancer death in the U.S. with survival restricted to a subset of those patients able to undergo surgical resection. However, even with surgery, recurrence rates range from 30% to 60%, depending on the pathologic stage. With the advent of partially effective, but potentially toxic adjuvant chemotherapy, it has become increasingly important to discover biomarkers that will identify those patients who have the highest likelihood of recurrence and who thus might benefit most from adjuvant chemotherapy. Hundreds of papers have appeared over the past several decades proposing a variety of molecular markers or proteins that may have prognostic significance in non–small cell lung cancer. This review analyzes the largest and most rigorous of these studies with the aim of compiling the most important prognostic markers in early stage non–small cell lung cancer. In this review, we focused on biomarkers primarily involved in one of three major pathways: cell cycle regulation, apoptosis, and angiogenesis. Although no single marker has yet been shown to be perfect in predicting patient outcome, a profile based on the best of these markers may prove useful in directing patient therapy. The markers with the strongest evidence as independent predictors of patient outcome include cyclin E, cyclin B1, p21, p27, p16, survivin, collagen XVIII, and vascular endothelial cell growth factor.
Abstract 5376: Identification of the first small molecule PRMT6 inhibitor tool compound
Authors: Allison Drew, Lorna Mitchell, Nathalie Rioux, Kerren Swinger, Scott Ribich, Suzanne Jacques-O'hagan, Trupti Lingaraj, Tim Wigle, Tom Riera, Richard Chesworth, Jesse Smith
Journal: Cancer Research (2015)

Abstract PRMT6 is a nuclear-localized arginine methyl transferase (RMT) capable of adding omega-N(G)-monomethylarginine and asymmetric omega-N(G),N(G)-dimethylarginine derivatives to histone and other protein substrates containing a GAR motif. PRMT6 can methylate both histone and non-histone substrates and is the only RMT known to methylate the H3R2 mark. This mark can act in opposition to the activating H3K4me3 mark, effectively acting as a transcriptional repressor. PRMT6 overexpression has been reported in several cancer types including melanoma and bladder, lung, and prostate carcinoma suggesting that inhibition of PRMT6 activity might have therapeutic utility. However, until now no small molecule PRMT6 inhibitor has been available to carry out in vitro and in vivo studies. Here we report identification of an aryl pyrazole as the first small molecule PRMT6 inhibitor. This tool compound has an IC50 of 10nM in a PRMT6 biochemical assay and the binding mode has been elucidated through crystallography. The compound inhibited methylation of H3R2 in a dose dependent manner in an engineered model in which PRMT6 was transiently expressed in the A375 cell line. The tool compound showed a half-life (t½) of 8.54 ± 1.43 h after a 1 mg/kg intravenous administration to rats and bioavailability of 65.6 ± 4.3% for a 5 mg/kg subcutaneous dose, enabling its use in further in vitro and in vivo target validation. Citation Format: Allison Drew, Lorna Mitchell, Nathalie Rioux, Kerren Swinger, Scott Ribich, Suzanne Jacques-O'hagan, Trupti Lingaraj, Tim Wigle, Tom Riera, Richard Chesworth, Jesse Smith. Identification of the first small molecule PRMT6 inhibitor tool compound. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5376. doi:10.1158/1538-7445.AM2015-5376
IN VITRO HEPATOCYTE REACTIVE OXYGEN SPECIES PRODUCTION IS NOT RELATED TO THE DEGREE OF FAT ACCUMULATION
Authors: Khalida A. Lockman, James P. Baren, Celine Filippi, Christopher Pemberton, Alexander F. Howie, Patricia Lee, Pauline Cowan, Anne Pryde, Alan J. Jaap, Peter C. Hayes, John N. Plevris
Journal: Hepatology (2008)
The Monitoring of DNA Adducts as an Approach to Carcinogen Detection
Authors: I. Bernard Weinstein
Journal: Annual Review of Public Health (1983)

Introduction It is now axiomatic in cancer research that a number of chemical carcino­ gens (particularly those that act as initiators) yield electrophiles, either spontaneously or via metabolic activation, that form covalent adducts with nucleophilic residues in cellular DNA. There is also considerable evidence that these reactions represent a critical event in the carcinogenic process (for review see 8, 17). With several carcinogens, the chemistry and steric aspects of these adducts have been elucidated in considerable detail. The simple alkylating agents can methylate or ethylate any of the nitrogens or oxygens in all four bases in DNA, as well as the sugar residues and phos­ phates of the DNA backbone (14). Although the N-7 position of guanine is generally the most extensive site of modification, current evidence indi­ cates that the 06 position is the most significant site of attack with respect to mutagenesis and carcinogenesis. The major DNA adducts produced by certain polycyclic carcinogens are shown in Figure 1. Activated derivatives of certain aromatic amines attack the C-8 position of guanine, as well as the N-2 position; the epoxide derivatives of benzo(a)pyrene (BP) and dimethyl­ (a)anthracene (DMBA) attack the N-2 position of guanine; and to a lesser extent the BP metabolite forms adducts with adenine and cytosine. Thus, the theme that emerges is that different carcinogens can attack different sites on the DNA, and that even a single carcinogen can form multiple types of adducts. This considerably complicates attempts to formulate a unified or simple theory relating specific types of DNA damage to the mechanism of carcinogenesis. There is evidence, however, that the major DNA adducts formed by activated derivatives of BP, aflatoxin, and certain nitrosamines are generally the same in diverse species and tissues, thus providing some unity to the comparative chemistry of carcinogen-DNA adducts. Studies
Human Studies of Angiogenic Gene Therapy
Authors: Rajesh Gupta, Jörn Tongers, Douglas W. Losordo
Journal: Circulation Research (2009)

Abstract : Despite significant advances in medical, interventional, and surgical therapy for coronary and peripheral arterial disease, the burden of these illnesses remains high. To address this unmet need, the science of therapeutic angiogenesis has been evolving for almost two decades. Early preclinical studies and phase I clinical trials achieved promising results with growth factors administered as recombinant proteins or as single-agent gene therapies, and data accumulated through 10 years of clinical trials indicate that gene therapy has an acceptable safety profile. However, more rigorous phase II and phase III clinical trials have failed to unequivocally demonstrate that angiogenic agents are beneficial under the conditions and in the patients studied to date. Investigators have worked to understand the biology of the vascular system and to incorporate their findings into new treatments for patients with ischemic disease. Recent gene- and cell-therapy trials have demonstrated the bioactivity of several new agents and treatment strategies. Collectively, these observations have renewed interest in the mechanisms of angiogenesis and deepened our understanding of the complexity of vascular regeneration. Gene therapy that incorporates multiple growth factors, approaches that combine cell and gene therapy, and the administration of “master switch” agents that activate numerous downstream pathways are among the credible and plausible steps forward. In this review, we examine the clinical development of angiogenic gene therapy, summarize several of the lessons learned during the conduct of these trials, and suggest how this prior experience may guide the conduct of future preclinical investigations and clinical trials.
Functional Microsatellite Polymorphism Associated with Divergent Social Structure in Vole Species
Authors: E. A. D. Hammock
Journal: Molecular Biology and Evolution (2004)

Forebrain vasopressin/vasotocin systems regulate a diverse set of complex social behaviors in a species-specific manner. Among mammals, vasopressin gene sequences and peptide distributions in the brain are highly conserved across species. In contrast, vasopressin V1a receptors (V1aR) are conserved at the protein level, but not at the level of gene structure or neuroanatomical distribution of the receptor. Here, we examine the functional role of a microsatellite segment in the 5′ region of V1aR that differs significantly between monogamous and nonmonogamous vole species with divergent V1aR expression patterns. Using luciferase reporter assays, we demonstrate that this microsatellite plays a significant role in transcriptional regulation in a cell-type–specific manner. These results suggest that significant evolutionary changes in social behavior can occur through variation in regulatory regions of genes already involved in social behavior.
Cardiac-Resynchronization Therapy for Mild-to-Moderate Heart Failure
Authors: Anthony S.L. Tang, George A. Wells, Mario Talajic, Malcolm O. Arnold, Robert Sheldon, Stuart Connolly, Stefan H. Hohnloser, Graham Nichol, David H. Birnie, John L. Sapp, Raymond Yee, Jeffrey S. Healey, Jean L. Rouleau
Journal: New England Journal of Medicine (2010)

Cardiac-resynchronization therapy (CRT) benefits patients with left ventricular systolic dysfunction and a wide QRS complex. Most of these patients are candidates for an implantable cardioverter-defibrillator (ICD). We evaluated whether adding CRT to an ICD and optimal medical therapy might reduce mortality and morbidity among such patients.We randomly assigned patients with New York Heart Association (NYHA) class II or III heart failure, a left ventricular ejection fraction of 30% or less, and an intrinsic QRS duration of 120 msec or more or a paced QRS duration of 200 msec or more to receive either an ICD alone or an ICD plus CRT. The primary outcome was death from any cause or hospitalization for heart failure.We followed 1798 patients for a mean of 40 months. The primary outcome occurred in 297 of 894 patients (33.2%) in the ICD-CRT group and 364 of 904 patients (40.3%) in the ICD group (hazard ratio in the ICD-CRT group, 0.75; 95% confidence interval [CI], 0.64 to 0.87; P<0.001). In the ICD-CRT group, 186 patients died, as compared with 236 in the ICD group (hazard ratio, 0.75; 95% CI, 0.62 to 0.91; P = 0.003), and 174 patients were hospitalized for heart failure, as compared with 236 in the ICD group (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). However, at 30 days after device implantation, adverse events had occurred in 124 patients in the ICD-CRT group, as compared with 58 in the ICD group (P<0.001).Among patients with NYHA class II or III heart failure, a wide QRS complex, and left ventricular systolic dysfunction, the addition of CRT to an ICD reduced rates of death and hospitalization for heart failure. This improvement was accompanied by more adverse events. (Funded by the Canadian Institutes of Health Research and Medtronic of Canada; ClinicalTrials.gov number, NCT00251251.).
The effect of antigen dose on CD4+ T helper cell phenotype development in a T cell receptor-alpha beta-transgenic model.
Authors: N A Hosken, K Shibuya, A W Heath, K M Murphy, A O'Garra
Journal: The Journal of Experimental Medicine (1995)

The dose of foreign antigen can influence whether a cell-mediated or humoral class of immune response is elicited, and this may be largely accounted for by the development of CD4+ T helper cells (Th) producing distinct sets of cytokines. The ability of antigen dose to direct the development of a Th1 or Th2 phenotype from naive CD4+ T cells, however, has not been demonstrated. In this report, we show that the antigen dose used in primary cultures could directly affect Th phenotype development from naive DO11.10 TCR-alpha beta-transgenic CD4+ T cells when dendritic cells or activated B cells were used as the antigen-presenting cells. Consistent with our previous findings, midrange peptide doses (0.3-0.6 microM) directed the development of Th0/Th1-like cells, which produced moderate amounts of interferon gamma (IFN-gamma). As the peptide dose was increased, development of Th1-like cells producing increased amounts of IFN-gamma was initially observed. At very high (&amp;gt; 10 microM) and very low (&amp;lt; 0.05 microM) doses of antigenic peptide, however, a dramatic switch to development of Th2-like cells that produced increasing amounts of interleukin 4 (IL-4) and diminishing levels of IFN-gamma was observed. This was true even when highly purified naive, high buoyant density CD4+ LECAM-1hi T cells were used, ruling out a possible contribution from contaminating "memory" phenotype CD4+ T cells. Neutralizing anti-IL-4 antibodies completely inhibited the development of this Th2-like phenotype at both high and low antigen doses, demonstrating a requirement for endogenous IL-4. Our findings suggest that the antigen dose may affect the levels of endogenous cytokines such as IL-4 in primary cultures, resulting in the development of distinct Th cell phenotypes.
Hypertrophic pulmonary osteoarthropathy and its occurrence with pulmonary metastases from renal carcinoma.
Authors: P Goldstraw, P R Walbaum
Journal: Thorax (1976)

The literature of hypertrophic pulmonary osteoarthropathy is reviewed with special reference to its occurrence with pulmonary metastases from extrathoracic tumours. The present theories on aetiology are discussed, and the relationship to finger clubbing and bronchogenic carcinoma is reviewed. A case is reported of hypertrophic osteoarthropathy as the presenting feature of pulmonary metastases from renal carcinoma, and of its relief by pulmonary resection.
Effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes
Authors: S. D West, D. J Nicoll, T. M Wallace, D. R Matthews, J. R Stradling
Journal: Thorax (2007)

<h3>Background:</h3> The effects of continuous positive airway pressure (CPAP) for obstructive sleep apnoea (OSA) on insulin resistance are not clear. Trials have found conflicting results and no appropriate control groups have been used. <h3>Methods:</h3> Forty-two men with known type 2 diabetes and newly diagnosed OSA (&gt;10 dips/h in oxygen saturation of &gt;4%) were randomised to receive therapeutic (n = 20) or placebo CPAP (n = 22) for 3 months. Baseline tests were performed and repeated after 3 months. The study was double blind. <h3>Results:</h3> Results are expressed as mean (SD). CPAP improved the Epworth sleepiness score significantly more in the therapeutic group than in the placebo group (−6.6 (4.5) vs −2.6 (4.9), p = 0.01). The maintenance of wakefulness test improved significantly in the therapeutic group but not in the placebo group (+10.6 (13.9) vs −4.7 (11.8) min, p = 0.001). Glycaemic control and insulin resistance did not significantly change in either the therapeutic or placebo groups: HbA1c (−0.02 (1.5) vs +0.1 (0.7), p = 0.7, 95% CI −0.6% to +0.9%), euglycaemic clamp (M/I: +1.7 (14.1) vs −5.7 (14.8), p = 0.2, 95% CI −1.8 to +0.3 l/kg/min<sup>1000</sup>), HOMA-%S (−1.5 (2.3) vs −1.1 (1.8), p = 0.2, 95% CI −0.3% to +0.08%) and adiponectin (−1.1 (1.2) vs −1.1 (1.3), p = 0.2, 95% CI −0.7 to +0.6 μg/ml). Body mass index, bioimpedance and anthropometric measurements were unchanged. Hours of CPAP use per night were 3.6 (2.8) in the treatment group and 3.3 (3.0) in the placebo group (p = 0.8). There was no correlation between CPAP use and the measures of glycaemic control or insulin resistance. <h3>Conclusion:</h3> Therapeutic CPAP does not significantly improve measures of glycaemic control or insulin resistance in men with type 2 diabetes and OSA.