tbuckley/cabot-search huggingface dataset:
miR-375 activates p21 and suppresses telomerase activity by coordinately regulating HPV E6/E7, E6AP, CIP2A, and 14-3-3ζ
Authors: Hyun Min Jung, Brittany L Phillips, Edward KL Chan
Journal: Molecular Cancer (2014)

While microRNAs (miRNAs) are extensively studied in post-transcriptional regulation of gene expressions in many biological processes, cellular miRNA-mediated regulation of viral genes remains unclear. In particular, the interplay between human papillomavirus (HPV) genes and miRNAs and how these interactions contribute to HPV-associated cancers remain elusive. Transient transfection of miR-375-mimic was used to compensate the loss-of-function of miR-375 in HPV-positive cancer. Regulation of oncogenic molecules and their downstream molecules via miR-375 in HPV-positive cancer was investigated using qRT-PCR, western blot, dual luciferase assay, indirect immunofluorescence analysis. All experiments were conducted at least three times to achieve statistical significance determined by Student t-test. In this study, we demonstrated how miR-375 negatively regulates HPV16 and 18 transcripts. We also found a cellular protein, E6-associated protein (E6AP), directly regulated by miR-375. miR-375-mediated repression of HPV transcripts and E6AP elevated major tumor suppressors p53, p21, and retinoblastoma protein 1 (RB). Cooperative regulation of miR-375 targets along with the increase of tumor suppressors led to ~60% reduction of telomerase reverse transcriptase (TERT) transcription followed by ~35% decrease of telomerase activity. Furthermore, miR-375-mediated regulation of 14-3-3ζ contributes to decrease telomerase activity by altering nuclear translocation of TERT. Taken together, miR-375-mediated suppression of multiple oncogenic components in HPV-associated carcinogenesis generates a cumulative biological response to rescue key tumor suppressors and diminish telomerase activity, which results in cell cycle arrest and cell proliferation inhibition.
Products of the “x” gene in hepatitis B and related viruses
Authors: Mark A. Feitelson
Journal: Hepatology (1986)

The X region in hepatitis B virus DNA potentially encodes a polypeptide 154 amino acids in length. Two synthetic peptides spanning residues 100 to 115 (peptide 99) and 115 to 131 (peptide 100) in a hydrophilic domain within the carboxy terminal third of theproposed gene product were made and used to raise peptide antisera in rabbits. Such antisera specifically bound to X reactive determinants in liver–derived core antigen particles from humans (HBcAg), ducks (DHBcAg), ground squirrels (GSHcAg) and woodchucks (WHcAg) at each step of core antigen purification. This reactivity was blocked by addition of excess synthetic peptide, and neither sera were reactive with other purified antigens such as HBsAg. Individual polypeptides associated with these core particles were also reactive by Western blotting. These findings suggest that X reactive determinants are present in the core particles of hepatitis B virus and related viruses, and thatone or more coreassociated polypeptides may have both X and core antigenic determinants. The possible significance of these observations upon the genetic organization and expression of the X gene is discussed.
Nephrology Visits and Health Care Resource Use Before and After Reporting Estimated Glomerular Filtration Rate
Authors: Brenda R. Hemmelgarn
Journal: JAMA (2010)

Laboratory reporting of estimated glomerular filtration rate (GFR) has been widely implemented, with limited evaluation.To examine trends in nephrologist visits and health care resource use before and after estimated GFR reporting.Community-based cohort study (N = 1,135,968) with time-series analysis. Participants were identified from a laboratory registry in Alberta, Canada, and followed up from May 15, 2003, to March 14, 2007 (with estimated GFR reporting implemented October 15, 2004).Nephrologist visits and patient management.Following estimated GFR reporting, the rate of first outpatient visits to a nephrologist for patients with chronic kidney disease (CKD; estimated GFR <60 mL/min/1.73 m(2)) increased by 17.5 (95% confidence interval [CI], 16.5-18.6) visits per 10,000 CKD patients per month, corresponding to a relative increase from baseline of 68.4% (95% CI, 65.7%-71.2%). There was no association between estimated GFR reporting and rate of first nephrologist visit among patients without CKD. Among patients with an estimated GFR of less than 30 mL/min/1.73 m(2), the rate of first nephrologist visits increased by 134.4 (95% CI, 60.0-208.7) visits per 10,000 patients per month. This increase was predominantly seen in women, patients aged 46 to 65 years as well as those aged 86 years or older, and those with hypertension, diabetes, and comorbidity. Reporting of estimated GFR was not associated with increased rates of internal medicine or general practitioner visits or increased use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers among patients with CKD and proteinuria or the subgroup limited to patients with diabetes.Reporting of estimated GFR was associated with an increase in first nephrologist visits, particularly among patients with more severe kidney dysfunction, women, middle-aged and very elderly patients, and those with comorbidities. Any effect on outcomes remains to be shown.
Serum Amyloid A in Uremic HDL Promotes Inflammation
Authors: Thomas Weichhart, Chantal Kopecky, Markus Kubicek, Michael Haidinger, Dominik Döller, Karl Katholnig, Cacang Suarna, Philipp Eller, Markus Tölle, Christopher Gerner, Gerhard J. Zlabinger, Markus van der Giet, Walter H. Hörl, Roland Stocker, Marcus D. Säemann
Journal: Journal of the American Society of Nephrology (2012)

Uremia impairs the atheroprotective properties of HDL, but the mechanisms underlying why this occurs are unknown. Here, we observed that HDL isolated from healthy individuals inhibited the production of inflammatory cytokines by peripheral monocytes stimulated with a Toll-like receptor 2 agonist. In contrast, HDL isolated from the majority of patients with ESRD did not show this anti-inflammatory property; many HDL samples even promoted the production of inflammatory cytokines. To investigate this difference, we used shotgun proteomics to identify 49 HDL-associated proteins in a uremia-specific pattern. Proteins enriched in HDL from patients with ESRD (ESRD-HDL) included surfactant protein B (SP-B), apolipoprotein C-II, serum amyloid A (SAA), and α-1-microglobulin/bikunin precursor. In addition, we detected some ESRD-enriched proteins in earlier stages of CKD. We did not detect a difference in oxidation status between HDL isolated from uremic and healthy patients. Regarding function of these uremia-specific proteins, only SAA mimicked ESRD-HDL by promoting inflammatory cytokine production. Furthermore, SAA levels in ESRD-HDL inversely correlated with its anti-inflammatory potency. In conclusion, HDL has anti-inflammatory activities that are defective in uremic patients as a result of specific changes in its molecular composition. These data suggest a potential link between the high levels of inflammation and cardiovascular mortality in uremia.
Production of type I interferons
Authors: Carine Asselin-Paturel, Giorgio Trinchieri
Journal: The Journal of Experimental Medicine (2005)

Plasmacytoid dendritic cells (pDCs) are specialized producers of type I interferons (IFNs) that respond to most viruses. Because of their antiviral activity and regulatory functions in innate and adaptive immunity, type I IFNs are important not only for antiviral resistance but also in other types of infections and in immune pathology. Here we discuss recent data that begin to reveal the unique molecular mechanisms underlying the remarkably rapid and efficient type I IFN production by pDCs.
Novel Histone Deacetylase Inhibitors in the Treatment of Thyroid Cancer
Authors: Constantine S. Mitsiades, Vassiliki Poulaki, Ciaran McMullan, Joseph Negri, Galinos Fanourakis, Athina Goudopoulou, Victoria M. Richon, Paul A. Marks, Nicholas Mitsiades
Journal: Clinical Cancer Research (2005)

Histone deacetylases (HDAC) and histone acetyltransferases exert opposing enzymatic activities that modulate the degree of acetylation of histones and other intracellular molecular targets, thereby regulating gene expression, cellular differentiation, and survival. HDAC inhibition results in accumulation of acetylated histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of two HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and m-carboxycinnamic acid bis-hydroxamide, on thyroid carcinoma cell lines, including lines originating from anaplastic and medullary carcinomas. In these models, both SAHA and m-carboxycinnamic acid bis-hydroxamide induced growth arrest and caspase-mediated apoptosis and increased p21 protein levels, retinoblastoma hypophosphorylation, BH3-interacting domain death agonist cleavage, Bax up-regulation, down-regulation of Bcl-2, A1, and Bcl-x(L) expression, and cleavage of poly(ADP-ribose) polymerase and caspase-8, -9, -3, -7, and -2. Transfection of Bcl-2 cDNA partially suppressed SAHA-induced cell death. SAHA down-regulated the expression of the apoptosis inhibitors FLIP and cIAP-2 and sensitized tumor cells to cytotoxic chemotherapy and death receptor activation. Our studies provide insight into the tumor type-specific mechanisms of antitumor effects of HDAC inhibitors and a framework for future clinical applications of HDAC inhibitors in patients with thyroid cancer, including histologic subtypes (e.g., anaplastic and medullary thyroid carcinomas) for which limited, if any, therapeutic options are available.
Clinical characteristics and corticosteroid treatment of acute eosinophilic pneumonia
Authors: Chin Kook Rhee, Kyung Hoon Min, Nam Yeol Yim, Ji Eun Lee, Na Rae Lee, Man Pyo Chung, Kyeongman Jeon
Journal: European Respiratory Journal (2012)

The clinical characteristics and optimal duration of corticosteroid treatment for acute eosinophilic pneumonia (AEP) have not been fully evaluated. This was a retrospective study of prospectively collected data from 137 patients with AEP, treated with standardised protocol, to clarify the clinical characteristics and compare the efficacies of 2 weeks versus 4 weeks of corticosteroid treatment for AEP. The majority of the patients altered their smoking habits within a median (interquartile range) of 17 (13-26) days prior to development of AEP. 80 (58%) patients presented with acute respiratory failure. A total of 127 (92%) patients were treated with corticosteroids: 4 weeks, n=42; 2 weeks, n=85. Major symptoms were resolved in 3 days and the severity of respiratory failure was inversely correlated with clinical outcomes. After adjusting for differences in baseline characteristics between the groups, the differences in adjusted mean (95% confidence interval) for resolution of dyspnoea and disappearance of all symptoms were 0.57 (-0.71-1.86) and -0.04 (-1.91-1.83) days, respectively. The difference in adjusted proportion of resolution of radiological abnormalities was 6.92% (-8.19-22.02). In conclusion, the duration of corticosteroid treatment could be shortened to 2 weeks, even in patients with respiratory failure.
Regulation of circulating immune complexes by complement receptor type 1 on erythrocytes in chronic viral liver diseases
Authors: J Miyaike
Journal: Gut (2002)

Complement receptor type 1 (CR1) is a transmembrane protein, and human erythrocyte CR1 (E-CR1) is involved in the transport of circulating immune complexes (IC) from the circulation to the reticuloendothelial system, including the liver and spleen. In chronic viral hepatitis, increased levels of IC containing viral particles and an association with various extrahepatic manifestations have been reported. However, regulatory mechanisms for IC levels are not fully understood. PATIENTS/SUBJECTS AND METHODS: We analysed IC, E-CR1, and quantitative polymorphism of the CR1 gene in 149 patients with chronic viral liver diseases and in 64 normal blood donors using an enzyme linked immunosorbent assay, radioimmunoassay, and polymerase chain reaction-restriction fragment length polymorphism, respectively. We also analysed the effect of CR1 gene polymorphism on IC binding to E-CR1 using molecular methods.E-CR1 levels in patients with chronic hepatitis and chronic viral liver diseases as a whole correlated inversely with increased levels of IC. Moreover, significantly high levels of IC were observed in patients with chronic hepatitis C (CH-C) who were homozygous for the E-CR1 low density allele. We also found low levels of E-CR1 in liver cirrhosis and CH-C but not in CH-B. Low levels of E-CR1 in CH-C were observed, even after considering the polymorphism of the CR1 gene. Finally, we demonstrated CR1 gene polymorphism dependent binding of hepatitis virus containing IC.Our results emphasise the important role of E-CR1 in clearance of IC from the circulation and the acquired, rather than inherited, decrease in E-CR1 in chronic viral liver diseases, especially of type C.
Correlation of forced oscillation technique in preschool children with cystic fibrosis with pulmonary inflammation
Authors: S Brennan
Journal: Thorax (2005)

<b>Background:</b> Lung disease in cystic fibrosis (CF) is established in early childhood with recurrent bacterial infections and inflammation. Using spirometry, the effect of this early lung damage cannot be measured until a child is 6 years of age when some irreversible lung damage may already have occurred. Techniques for measurement of lung function in infants and young children include raised volume rapid thoracic compression (RVRTC) and low frequency forced oscillation (LFFOT). The aim of this study was to investigate the role of inflammation and infection on a population of infants and young children with CF and to determine whether lung function in this population (measured by LFFOT) is affected by early lung disease. <b>Methods:</b> Lung function was measured by LFFOT in 24 children undergoing bronchoalveolar lavage (BAL) on 27 occasions as part of an annual programme while still under general anaesthesia. Following lung function testing, three aliquots of saline were instilled into the right middle or lower lobe. The first aliquot retrieved was processed for the detection of microbes, and the remaining aliquots were pooled to assess inflammatory markers (cytology, IL-8, NE, LTB<sub>4</sub>). <b>Results:</b> Inflammation (percentage and number of neutrophils) was significantly higher in children with infections (p&lt;0.001, p = 0.04, respectively), but not in those with symptoms. Several markers of inflammation significantly correlated with LFFOT parameters (R, G, and η). <b>Conclusion:</b> Infections and inflammation are established before symptoms are apparent. Inflammation is correlated with measures of parenchymal changes in lung function measured by LFFOT.
Predictive Value of Serial High‐Resolution Computed Tomography Analyses and Concurrent Lung Function Tests in Systemic Sclerosis
Authors: Anna‐Maria Hoffmann‐Vold, Trond M. Aaløkken, May Brit Lund, Torhild Garen, Øyvind Midtvedt, Cathrine Brunborg, Jan Tore Gran, Øyvind Molberg
Journal: Arthritis & Rheumatology (2015)

Objective Systemic sclerosis (SSc) carries a high risk of progressive interstitial lung disease (ILD), but tools for stratifying individual risk are scarce. The purpose of this study was to assess detailed data from serial lung fibrosis measurements and paired pulmonary function tests (PFTs) as outcome prediction tools in a prospective cohort of SSc patients. Methods Paired PFTs and high‐resolution computed tomography (HRCT) scans were obtained at baseline and at followup in 305 SSc patients who met the American College of Rheumatology/European League Against Rheumatism 2013 classification criteria. The extent of fibrosis was scored on 10 sections from every HRCT scan and expressed as the percentage of the total lung volume. Results Baseline HRCT analyses revealed 3 SSc subgroups: those with &gt;20% lung fibrosis (n = 40), those with 1–20% fibrosis (n = 157), and those with no fibrosis (n = 108). At followup HRCT (mean of 3.1 years later), all 108 group 3 patients were still free of fibrosis. In group 2 patients, 146 continued to have 1–20% fibrosis (group 2a), whereas 11 (marked by short disease duration of 1.3 years) had experienced progression to &gt;20% fibrosis (group 2b). The annual fibrosis progression rate differed across the 4 groups: 0.9% in group 1, 0.7% in group 2a, 5.9% in group 2b, and 0% in group 3. The annual fibrosis progression rate correlated with the total decline in the forced vital capacity (FVC) (7.1%, 5.7%, 8.7%, and 2.9% in groups 1, 2a, 2b, and 3, respectively), but not the diffusing capacity for carbon monoxide (DL co) (8.4%, 7.7%, 7.7%, and 8.6%, respectively). Multivariate analyses identified anticentromere antibodies (odds ratio [OR] 4.7) and baseline DL co (OR 1.04) as predictors of no fibrosis at followup and baseline fibrosis (OR 1.3) and FVC (OR 0.96) as predictors of &gt;20% fibrosis at followup. Conclusion These prospective cohort data suggest that HRCT performed at baseline predicts the development of fibrosis, the rate of progression of fibrosis, and the decline in pulmonary function in SSc.
A quantum of truth? Querying the alternative benchmark for human cognition
Authors: Ben R. Newell, Don van Ravenzwaaij, Chris Donkin
Journal: Behavioral and Brain Sciences (2013)

Abstract We focus on two issues: (1) an unusual, counterintuitive prediction that quantum probability (QP) theory appears to make regarding multiple sequential judgments, and (2) the extent to which QP is an appropriate and comprehensive benchmark for assessing judgment. These issues highlight how QP theory can fall prey to the same problems of arbitrariness that Pothos &amp; Busemeyer (P&amp;B) discuss as plaguing other models.
Cost-Effectiveness Analysis of Telemedicine to Evaluate Diabetic Retinopathy in a Prison Population
Authors: Noriaki Aoki, Kim Dunn, Tsuguya Fukui, J. Robert Beck, William J. Schull, Helen K. Li
Journal: Diabetes Care (2004)

OBJECTIVE—A cost-effectiveness analysis was conducted to investigate the clinical and economic impact of teleophthalmology in evaluating diabetic retinopathy in prison inmates with type 2 diabetes. RESEARCH DESIGN AND METHODS—Based on a hypothetical teleophthalmology system to evaluate diabetic retinopathy patients with type 2 diabetes in a prison care setting, a Markov decision model was developed with probability and cost data derived primarily from published epidemiological and outcome studies. A 40-year-old African-American man with type 2 diabetes was used as a reference case subject. The number of quality-adjusted life-years (QALYs) gained was used as the clinical outcome, and the cost in U.S. dollars from the year 2003 was used as the economic outcome. Teleophthalmology and nonteleophthalmology strategies were compared using an expected QALYs calculation and two types of sensitivity analyses: probabilistic and traditional n-way sensitivity analyses. RESULTS—The teleophthalmology strategy dominates in the cost-effectiveness analysis for the reference case subject: $16,514/18.73 QALYs for teleophthalmology and $17,590/18.58 QALYs for nonteleophthalmology. Ninety percent of the Monte Carlo simulations showed cost effectiveness (annual cost/QALYs ≤$50,000) in the teleophthalmology strategy based on an assumed inmate population. Teleophthalmology is the better strategy if the number of diabetic inmates in the prison community is &amp;gt;500. CONCLUSIONS—Our cost-effectiveness analysis demonstrates that teleophthalmology holds great promise to reduce the cost of inmate care and reduce blindness caused by diabetic retinopathy in type 2 diabetic patients.
Impaired activities of antioxidant enzymes elicit endothelial dysfunction in spontaneous hypertensive rats despite enhanced vascular nitric oxide generation
Authors: S ULKER, D MCMASTER, P MCKEOWN, U BAYRAKTUTAN
Journal: Cardiovascular Research (2003)

Objective: Enhanced oxidative stress is involved in mediating the endothelial dysfunction associated with hypertension. The aim of this study was to investigate the relative contributions of pro-oxidant and anti-oxidant enzymes to the pathogenesis of endothelial dysfunction in genetic hypertension. Methods: Dilator responses to endothelium-dependent and endothelium-independent agents such as acetylcholine (ACh) and sodium nitroprusside were measured in the thoracic aortas of 28-week-old spontaneously hypertensive rats (SHR) and their matched normotensive counterparts, Wistar Kyoto rats (WKY). The activity and expression (mRNA and protein levels) of endothelial nitric oxide synthase (eNOS), p22-phox, a membrane-bound component of NAD(P)H oxidase, and antioxidant enzymes, namely, superoxide dismutases (CuZn- and Mn-SOD), catalase and glutathione peroxidase (GPx), were also investigated in aortic rings. Results: Relaxant responses to ACh were attenuated in phenylephrine-precontracted SHR aortic rings, despite a 2-fold increase in eNOS expression and activity. Although the activity and/or expression of SODs, NAD(P)H oxidase (p22-phox) and GPx were elevated in SHR aorta, catalase activity and expression remained unchanged compared to WKY. Pretreatment of SHR aortic rings with the inhibitor of xanthine oxidase, allopurinol, and the inhibitor of cyclooxygenase, indomethacin, significantly potentiated ACh-induced relaxation. Pretreatment of SHR rings with catalase and Tiron, a superoxide anion (O2−) scavenger, increased the relaxant responses to the levels observed in WKY rings whereas pyrogallol, a O2−-generator, abolished relaxant responses to ACh. Conclusion: These data demonstrate that dysregulation of several enzymes, resulting in oxidative stress, contributes to the pathogenesis of endothelial dysfunction in SHR and indicate that the antioxidant enzyme catalase is of particular importance in the reversal of this defect.
Thymic epithelial cells provide unique signals for positive selection of CD4+CD8+ thymocytes in vitro.
Authors: G Anderson, J J Owen, N C Moore, E J Jenkinson
Journal: The Journal of Experimental Medicine (1994)

Using a novel system that supports positive selection in vitro, we have investigated the cellular requirements for this process by testing the ability of individual thymic and nonthymic stromal cell types to support the maturation of CD4+CD8+ thymocytes into CD4+ or CD8+ T cells. We show that thymic cortical epithelial cells are unique in their ability to mediate this maturation, and suggest that in addition to TCR ligation, these cells supply specific signals for positive selection. Moreover, by demonstrating positive selection on ECDI (1-ethyl-3-[3'dimethyl-aminopropyl]-carbodiimide)-fixed epithelial cells in this system, we provide direct evidence that the provision of these signals involves interactions with epithelial cell surface molecules rather than the release of soluble factors.