tbuckley/cabot-search huggingface dataset:
Systemic CD4+ and CD8+ T-cell cytokine profiles correlate with GOLD stage in stable COPD
Authors: Marthe S. Paats, Ingrid M. Bergen, Henk C. Hoogsteden, Menno M. van der Eerden, Rudi W. Hendriks
Journal: European Respiratory Journal (2011)

Chronic obstructive pulmonary disease (COPD) is associated with pulmonary and systemic inflammation. Both CD4+ and CD8+ T-lymphocytes play a key role in COPD pathogenesis, but cytokine profiles in circulating T-lymphocytes have not been well characterised. Here we report the analysis of peripheral blood T-cells from 30 stable COPD patients and 10 healthy never-smokers for interferon (IFN)-γ, interleukin (IL)-4, tumour necrosis factor (TNF)-α and the T-helper 17 cytokines IL-17A, IL-17F and IL-22 by intracellular flow cytometry. We found significantly increased proportions of IFN-γ+ and TNF-α+ CD8+ T-cells in COPD patients, when compared with healthy controls. This was most evident in patients with less severe disease. In contrast, expression profiles in circulating CD4+ T-cells were similar in COPD patients and healthy controls for all cytokines tested, except for IL-17F. COPD patients with more severely reduced diffusing capacity had lower proportions of IL-17A+ CD4+ T-cells. Proportions of IL-22+ cells in the CD4+ memory T-cell population were significantly increased in active smokers, when compared with past smokers. Collectively, this comprehensive cytokine analysis of circulating T-cells in COPD patients revealed a correlation for CD8+ T-cells between Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage and IFN-γ or TNF-α expression, but not for CD4+ T-cells.
Differential Roles of Interleukin 15 mRNA Isoforms Generated by Alternative Splicing in Immune Responses in Vivo
Authors: Hitoshi Nishimura, Toshiki Yajima, Yoshikazu Naiki, Hironaka Tsunobuchi, Masayuki Umemura, Keiko Itano, Tetsuya Matsuguchi, Misao Suzuki, Pamela S. Ohashi, Yasunobu Yoshikai
Journal: The Journal of Experimental Medicine (2000)

At least two types of interleukin (IL)-15 mRNA isoforms are generated by alternative splicing at the 5′ upstream of exon 5 in mice. To elucidate the potential roles of IL-15 isoforms in immune responses in vivo, we constructed two groups of transgenic mice using originally described IL-15 cDNA with a normal exon 5 (normal IL-15 transgenic [Tg] mice) and IL-15 cDNA with an alternative exon 5 (alternative IL-15 Tg mice) under the control of an MHC class I promoter. Normal IL-15 Tg mice constitutionally produced a significant level of IL-15 protein and had markedly increased numbers of memory type (CD44high Ly6C+) of CD8+ T cells in the LN. These mice showed resistance to Salmonella infection accompanied by the enhanced interferon (IFN)-γ production, but depletion of CD8+ T cells exaggerated the bacterial growth, suggesting that the IL-15–dependent CD8+ T cells with a memory phenotype may serve to protect against Salmonella infection in normal IL-15 Tg mice. On the other hand, a large amount of intracellular IL-15 protein was detected but hardly secreted extracellularly in alternative IL-15 Tg mice. Although most of the T cells developed normally in the alternative IL-15 Tg mice, they showed impaired IFN-γ production upon TCR engagement. The alternative IL-15 transgenic mice were susceptible to Salmonella accompanied by impaired production of endogenous IL-15 and IFN-γ. Thus, two groups of IL-15 Tg mice may provide information concerning the different roles of IL-15 isoforms in the immune system in vivo.
Effect of cimetidine, ranitidine, famotidine and omeprazole on hepatocyte proliferation in vitro
Authors: A. Francavilla, C. Panella, L. Polimeno, A. Di Leo, L. Makowka, M. Barone, A. Amoruso, M. Ingrosso, T.E. Starzl
Journal: Journal of Hepatology (1989)
Notch1 is an effector of Akt and hypoxia in melanoma development
Authors: Barbara Bedogni, James A. Warneke, Brian J. Nickoloff, Amato J. Giaccia, Marianne Broome Powell
Journal: Journal of Clinical Investigation (2008)

Melanomas are highly aggressive neoplasms resistant to most conventional therapies. These tumors result from the interaction of altered intracellular tumor suppressors and oncogenes with the microenvironment in which these changes occur. We previously demonstrated that physiologic skin hypoxia contributes to melanomagenesis in conjunction with Akt activation. Here we show that Notch1 signaling is elevated in human melanoma samples and cell lines and is required for Akt and hypoxia to transform melanocytes in vitro. Notch1 facilitated melanoma development in a xenograft model by maintaining cell proliferation and by protecting cells from stress-induced cell death. Hyperactivated PI3K/Akt signaling led to upregulation of Notch1 through NF-κB activity, while the low oxygen content normally found in skin increased mRNA and protein levels of Notch1 via stabilization of HIF-1α. Taken together, these findings demonstrate that Notch1 is a key effector of both Akt and hypoxia in melanoma development and identify the Notch signaling pathway as a potential therapeutic target in melanoma treatment.
Contribution of the nitric oxide-guanylyl cyclase system to circadian regulation of blood pressure in normotensive Wistar-Kyoto rats
Authors: K. Witte, A. Schnecko, P. Zuther, B. Lemmer
Journal: Cardiovascular Research (1995)

The study was performed in order to elucidate whether or not the nitric oxide-guanylyl cyclase system is involved in the circadian regulation of blood pressure.Basal and sodium nitroprusside-stimulated guanylyl cyclase activity was studied in vitro in aortic tissue from normotensive Wistar-Kyoto rats sacrificed at 7 circadian times. Effects of the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) on blood pressure and heart rate of rats were measured telemetrically after acute injection of L-NAME either in the morning or in the evening as well as after chronic application in drinking water.Guanylyl cyclase activity exhibited significant circadian rhythmicity under basal conditions and after stimulation by sodium nitroprusside 10 microM. Peaks in cGMP formation were observed in the daily resting period, i.e. the period of low blood pressure in rats. Acute application of L-NAME dose-dependently increased blood pressure; effects were more pronounced after injection in the morning than in the evening, leading to an inverse blood pressure profile after the highest dose (30 mg/kg i.p.). Chronic treatment with L-NAME resulted in a dose-dependent upward shift of the control blood pressure profile. Only at the highest dose applied in drinking water (100 mg/kg per day) was the circadian pattern in blood pressure altered, showing a reduced fall in the morning.Circadian rhythmicity in basal and stimulated soluble guanylyl cyclase activity and the reversed blood pressure profile after acute injections of L-NAME indicate an involvement of the nitric oxide-guanylyl cyclase system in circadian blood pressure regulation. After chronic inhibition of nitric oxide synthase additional and counterregulatory mechanisms have to be considered.
Changes in prevalence and load of airway bacteria using quantitative PCR in stable and exacerbated COPD
Authors: Davinder S Garcha, Sarah J Thurston, Anant R C Patel, Alexander J Mackay, James J P Goldring, Gavin C Donaldson, Timothy D McHugh, Jadwiga A Wedzicha
Journal: Thorax (2012)

Prevalence and load of airway bacteria in stable and exacerbated chronic obstructive pulmonary disease (COPD) has been previously studied using microbiological culture. Molecular techniques, such as quantitative PCR (qPCR), may be more informative.In this study, 373 sputum samples from 134 COPD outpatients were assessed for prevalence and load of typical airway bacteria (Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis) by multiplex qPCR, with 176 samples analysed for atypical bacteria. Paired stable and exacerbation typical bacteria data were compared in 52 patients. We compared routine culture with qPCR in 177/373 samples.Typical bacteria were more prevalent in exacerbation than stable-state paired samples: 30/52 (57.7%) vs. 14/52 (26.9%); p=0.001. In patients who were bacteria-positive at both time points, mean (±1 SEM) load was significantly higher at exacerbation than stable state (108.5(±0.3) vs. 107.2(±0.5) cfu/ml), constituting a 20-fold increase (p=0.011). qPCR was more discriminatory at detecting typical bacteria than microbiological culture (prevalence 59.3% vs. 24.3%; p<0.001). At stable state, higher airway bacterial load correlated with more severe airflow limitation (FEV(1)%predicted) (r=-0.299; p=0.033) and higher inhaled corticosteroid dosage (r=0.382; p=0.008). Mean C-reactive protein was higher in bacterial-associated exacerbations (35.0 Vs 25.1 mg/L; p=0.032).Airway bacterial prevalence and load increase at COPD exacerbations and are an aetiological factor. qPCR is more discriminatory than culture, identifying higher airway bacterial prevalence. Exacerbations associated with bacterial detection showed a higher mean C-reactive protein level. In the stable state, airway bacterial load is related to more severe airflow limitation and higher inhaled corticosteroid dosage used.
Hydroxyurea Induces Bystander Cytotoxicity in Cocultures of Herpes Simplex Virus Thymidine Kinase–Expressing and Nonexpressing HeLa Cells Incubated with Ganciclovir
Authors: Brian G. Gentry, Paul D. Boucher, Donna S. Shewach
Journal: Cancer Research (2006)

Abstract Suicide gene therapy with the herpes simplex virus thymidine kinase (HSV-TK) cDNA and ganciclovir can elicit cytotoxicity to transgene-expressing and nonexpressing bystander cells via transfer of ganciclovir phosphates through gap junctions. HeLa cells do not exhibit bystander cytotoxicity, although we showed recently that they transfer low levels of ganciclovir phosphates to bystander cells. Here, we attempted to induce bystander cytotoxicity using hydroxyurea, an inhibitor of ribonucleotide reductase, to decrease the endogenous dGTP pool, which should lessen competition with ganciclovir triphosphate for DNA incorporation. Addition of hydroxyurea to cocultures of HSV-TK-expressing and bystander cells synergistically increased ganciclovir-mediated cytotoxicity to both cell populations while producing primarily an additive effect in cultures of 100% HSV-TK-expressing cells. Whereas HSV-TK-expressing cells in coculture were ∼50-fold less sensitive to ganciclovir compared with cultures of 100% HSV-TK-expressing cells, addition of hydroxyurea restored ganciclovir sensitivity. Quantification of deoxynucleoside triphosphate pools showed that hydroxyurea decreased dGTP pools without significantly affecting ganciclovir triphosphate levels. Although hydroxyurea significantly increased the ganciclovir triphosphate:dGTP value for 12 to 24 hours in HSV-TK-expressing and bystander cells from coculture (1.4- to 4.9-fold), this value was increased for &amp;lt;12 hours (2.5-fold) in 100% HSV-TK-expressing cells. These data suggest that the prolonged increase in the ganciclovir triphosphate:dGTP value in cells in coculture resulted in synergistic cytotoxicity. Compared with enhancement of bystander cytotoxicity through modulation of gap junction intercellular communication, this strategy is superior because it increased cytotoxicity to both HSV-TK-expressing and bystander cells in coculture. This approach may improve clinical efficacy. (Cancer Res 2006; 66(7): 3845-51)
Intermittent High-Intensity Exercise Does Not Increase the Risk of Early Postexercise Hypoglycemia in Individuals With Type 1 Diabetes
Authors: Kym J. Guelfi, Timothy W. Jones, Paul A. Fournier
Journal: Diabetes Care (2005)

Exercise is generally recommended for individuals with type 1 diabetes because it is associated with numerous physiological (1,2) and psychological (3,4) benefits. However, participation in exercise can also increase the risk of experiencing severe hypoglycemia, during both exercise (5) and recovery (6). Unfortunately, there are no evidence-based guidelines for safe participation in intermittent high-intensity exercise (IHE), which characterizes most team and field sports, manual labor occupations, and spontaneous play in children. This is because the response of blood glucose levels to this type of exercise is not known, as previous research on intermittent exercise has employed exercise protocols that do not accurately reflect the high-intensity work–to–recovery ratios observed in intermittent sports (7,8). Therefore, the aim of this study was to investigate the effect of IHE that simulates the high-intensity work–to–recovery ratios observed in intermittent sports on blood glucose levels and glucoregulatory hormones in individuals with type 1 diabetes in order to assess the risk of hypoglycemia.

Eight volunteers with type 1 diabetes (aged [±SD] 18.6 ± 2.1 years, BMI 22.1 ± 1.5 kg/m2, V o2peak 42.4 ± 7.3 ml · kg−1 · min−1, type 1 diabetes duration 7.0 ± 4.6 years, and HbA1c 7.0 ± 0.4%), who were free of complications and not taking …
Global Alterations of DNA Methylation in Cholangiocarcinoma Target the Wnt Signaling Pathway
Authors: Benjamin Goeppert, Carolin Konermann, Christopher Roman Schmidt, Olga Bogatyrova, Lea Geiselhart, Christina Ernst, Lei Gu, Natalia Becker, Manuela Zucknick, Arianeb Mehrabi, Mohammadreza Hafezi, Frederick Klauschen, Albrecht Stenzinger, Arne Warth, Kai Breuhahn, Marcus Renner, Wilko Weichert, Peter Schirmacher, Christoph Plass, Dieter Weichenhan
Journal: Hepatology (2013)

The molecular mechanisms underlying the genesis of cholangiocarcinomas (CCs) are poorly understood. Epigenetic changes such as aberrant hypermethylation and subsequent atypical gene expression are characteristic features of most human cancers. In CC, data regarding global methylation changes are lacking so far. We performed a genome-wide analysis for aberrant promoter methylation in human CCs. We profiled 10 intrahepatic and 8 extrahepatic CCs in comparison to non-neoplastic biliary tissue specimens, using methyl-CpG immunoprecipitation (MCIp) combined with whole-genome CpG island arrays. DNA methylation was confirmed by quantitative mass spectrometric analysis and functional relevance of promoter hypermethylation was shown in demethylation experiments of two CC cell lines using 5-aza-2′deoxycytidine (DAC) treatment. Immunohistochemical staining of tissue microarrays (TMAs) from 223 biliary tract cancers (BTCs) was used to analyze candidate gene expression at the protein level. Differentially methylated, promoter-associated regions were nonrandomly distributed and enriched for genes involved in cancer-related pathways including Wnt, transforming growth factor beta (TGF-β), and PI3K signaling pathways. In CC cell lines, silencing of genes involved in Wnt signaling, such as SOX17, WNT3A , DKK2 , SFRP1, SFRP2 , and SFRP4 was reversed after DAC administration. Candidate protein SFRP2 was substantially down-regulated in neoplastic tissues of all BTC subtypes as compared to normal tissues. A significant inverse correlation of SFRP2 protein expression and pT status was found in BTC patients. Conclusion : We provide a comprehensive analysis to define the genome-wide methylation landscape of human CC. Several candidate genes of cancer-relevant signaling pathways were identified, and closer analysis of selected Wnt pathway genes confirmed the relevance of this pathway in CC. The presented global methylation data are the basis for future studies on epigenetic changes in cholangiocarcinogenesis. (Hepatology 2014;59:544–554)
Feasibility and pharmacokinetic study of a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) in relapsed B-cell lymphoma
Authors: K. Tobinai, Y. Kobayashi, M. Narabayashi, M. Ogura, Y. Kagami, Y. Morishima, T. Ohtsu, T. Igarashi, Y. Sasaki, T. Kinoshita, T. Murate
Journal: Annals of Oncology (1998)
The Case against a Smoker's License
Authors: Jeff Collin
Journal: PLoS Medicine (2012)

Background to the debate Tobacco continues to kill millions of people around the world each year and its use is increasing in some countries, which makes the need for new, creative, and radical efforts to achieve the tobacco control endgame vitally important. One such effort is discussed in this PLOS Medicine Debate, where Simon Chapman presents his proposal for a "smoker's license" and Jeff Collin argues against. Chapman sets out a case for introducing a smart card license for smokers designed to limit access to tobacco products and encourage cessation. Key elements of the smoker's license include smokers setting daily limits, financial incentives for permanent license surrender, and a test of health risk knowledge for commencing smokers. Collin argues against the proposal, saying that it would shift focus away from the real vector of the epidemic—the tobacco industry—and that by focusing on individuals it would censure victims, increase stigmatization of smokers, and marginalize the poor.
Comparative Genomics Suggests That an Ancestral Polyploidy Event Leads to Enhanced Root Nodule Symbiosis in the Papilionoideae
Authors: Qi-Gang Li, Li Zhang, Chun Li, Jim M. Dunwell, Yuan-Ming Zhang
Journal: Molecular Biology and Evolution (2013)

Root nodule symbiosis (RNS) is one of the most efficient biological systems for nitrogen fixation and it occurs in 90% of genera in the Papilionoideae, the largest subfamily of legumes. Most papilionoid species show evidence of a polyploidy event that occurred approximately 58 Ma. Although polyploidy is considered to be an important evolutionary force in plants, the role of this papilionoid polyploidy event, especially its association with RNS, is not understood. In this study, we explored this role using an integrated comparative genomic approach and conducted gene expression comparisons and gene ontology enrichment analyses. The results show the following: 1) Approximately a quarter of the papilionoid-polyploidy–derived duplicate genes are retained; 2) there is a striking divergence in the level of expression of gene duplicate pairs derived from the polyploidy event; and 3) the retained duplicates are frequently involved in the processes crucial for RNS establishment, such as symbiotic signaling, nodule organogenesis, rhizobial infection, and nutrient exchange and transport. Thus, we conclude that the papilionoid polyploidy event might have further refined RNS and induced a more robust and enhanced symbiotic system. This conclusion partly explains the widespread occurrence of the Papilionoideae.
The Pulmonary Capillary Bed in Various Forms of Pulmonary Hypertension
Authors: R. MICHAEL MCCREDIE
Journal: Circulation (1966)

Pulmonary diffusing capacity for CO (D L ), membrane diffusing capacity (D M ), and pulmonary capillary blood volume (V c ) were measured in 44 patients with various forms and severity of pulmonary vascular disease, and these measurements were compared with hemodynamic data obtained at cardiac catheterization, with clinical disability, and, in 27 patients, with the results of corrective cardiac surgery. In 11 of these patients, D L , D M , and V c were remeasured up to 8 months after cardiac surgery. In general, the diffusing characteristics and pressure-volume relationships in this larger group confirmed the previously reported findings in mitral valve disease. 1 D M was impaired in almost all cases regardless of etiology or severity. Most of the 11 patients restudied showed no change in D L , D M , or V c up to 8 months after surgery. Reduction in V c correlated well both with clinical disability and with surgical results. Two patients with primary pulmonary hypertension and three of the four patients with equally severe pulmonary hypertension due to mitral valve disease had high V c relative to pulmonary vascular resistance. If the measurements of V c are not falsely high, then it appears that the capillary bed makes relatively and absolutely less contribution to the total rise in pulmonary vascular resistance in these patients. This could be explained by intense precapillary vasoconstriction in the presence of a relatively normal pulmonary capillary bed.
Twenty-four–hour Ambulatory Blood Pressure in Children with Sleep-disordered Breathing
Authors: Raouf S. Amin, John L. Carroll, Jenny L. Jeffries, Charles Grone, Judy A. Bean, Barbara Chini, Ronald Bokulic, Stephen R. Daniels
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Obstructive sleep apnea causes intermittent elevation of systemic blood pressure (BP) during sleep. To determine whether obstructive apnea in children has a tonic effect on diurnal BP, 24-hour ambulatory blood pressure was obtained from 60 children with mean age of 10.8 +/- 3.5 years. Thirty-nine children had obstructive apnea and 21 had primary snoring. Children with obstructive apnea had significantly greater mean BP variability during wakefulness and sleep, a higher night-to-day systolic BP, and a smaller nocturnal dipping of mean BP. Variability of mean arterial pressure during wakefulness was predicted by the desaturation, body mass, and arousal indices, whereas variability during sleep was predicted by apnea-hypopnea and body mass indices. Nocturnal BP dipping was predicted by the desaturation index. There were no significant differences in systolic, diastolic, or mean arterial BP during sleep between the groups. Diastolic BP during wakefulness was significantly different between the groups and correlated negatively with apnea-hypopnea index. We conclude that obstructive apnea in children is associated with 24-hour BP dysregulation and that, independent of obesity, the frequency of obstructive apnea, oxygen desaturation, and arousal contributes to abnormal BP control.
Failure to Rescue in Safety-Net Hospitals
Authors: Elliot Wakeam, Nathanael D. Hevelone, Rebecca Maine, Jabaris Swain, Stuart A. Lipsitz, Samuel R. G. Finlayson, Stanley W. Ashley, Joel S. Weissman
Journal: JAMA Surgery (2014)

Failure to rescue (FTR), the mortality rate among surgical patients with complications, is an emerging quality indicator. Hospitals with a high safety-net burden, defined as the proportion of patients covered by Medicaid or uninsured, provide a disproportionate share of medical care to vulnerable populations. Given the financial strains on hospitals with a high safety-net burden, availability of clinical resources may have a role in outcome disparities.To assess the association between safety-net burden and FTR and to evaluate the effect of clinical resources on this relationship.A retrospective cohort of 46,519 patients who underwent high-risk inpatient surgery between January 1, 2007, and December 31, 2010, was assembled using the Nationwide Inpatient Sample. Hospitals were divided into the following 3 safety-net categories: high-burden hospitals (HBHs), moderate-burden hospitals (MBHs), and low-burden hospitals (LBHs). Bivariate and multivariate analyses controlling for patient, procedural, and hospital characteristics, as well as clinical resources, were used to evaluate the relationship between safety-net burden and FTR.FTR.Patients in HBHs were younger (mean age, 65.2 vs 68.2 years; P = .001), more likely to be of black race (11.3% vs 4.2%, P < .001), and less likely to undergo an elective procedure (39.3% vs 48.6%, P = .002) compared with patients in LBHs. The HBHs were more likely to be large, major teaching facilities and to have high levels of technology (8.6% vs 4.0%, P = .02), sophisticated internal medicine (7.7% vs 4.3%, P = .10), and high ratios of respiratory therapists to beds (39.7% vs 21.1%, P < .001). However, HBHs had lower proportions of registered nurses (27.9% vs 38.8%, P = .02) and were less likely to have a positron emission tomographic scanner (15.4% vs 22.0%, P = .03) and a fully implemented electronic medical record (12.6% vs 17.8%, P = .03). Multivariate analyses showed that HBHs (adjusted odds ratio, 1.35; 95% CI, 1.19-1.53; P < .001) and MBHs (adjusted odds ratio, 1.15; 95% CI, 1.05-1.27; P = .005) were associated with higher odds of FTR compared with LBHs, even after adjustment for clinical resources.Despite access to resources that can improve patient rescue rates, HBHs had higher odds of FTR, suggesting that availability of hospital clinical resources alone does not explain increased FTR rates.