tbuckley/cabot-search huggingface dataset:
Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients
Authors: Deepti Malhotra, Rajesh K. Thimmulappa, Nicolas Mercado, Kazuhiro Ito, Ponvijay Kombairaju, Sarvesh Kumar, Jinfang Ma, David Feller-Kopman, Robert Wise, Peter Barnes, Shyam Biswal
Journal: Journal of Clinical Investigation (2011)

Chronic obstructive pulmonary disease (COPD), which is caused primarily by cigarette smoking, is a major health problem worldwide. The progressive decline in lung function that occurs in COPD is a result of persistent inflammation of the airways and destruction of the lung parenchyma. Despite the key role of inflammation in the pathogenesis of COPD, treatment with corticosteroids — normally highly effective antiinflammatory drugs — has little therapeutic benefit. This corticosteroid resistance is largely caused by inactivation of histone deacetylase 2 (HDAC2), which is critical for the transrepressive activity of the glucocorticoid receptor (GR) that mediates the antiinflammatory effect of corticosteroids. Here, we show that in alveolar macrophages from patients with COPD, S-nitrosylation of HDAC2 is increased and that this abolishes its GR-transrepression activity and promotes corticosteroid insensitivity. Cys-262 and Cys-274 of HDAC2 were found to be the targets of S-nitrosylation, and exogenous glutathione treatment of macrophages from individuals with COPD restored HDAC2 activity. Treatment with sulforaphane, a small-molecule activator of the transcription factor nuclear factor erythroid 2–related factor 2 (NRF2), was also able to denitrosylate HDAC2, restoring dexamethasone sensitivity in alveolar macrophages from patients with COPD. These effects of sulforaphane were glutathione dependent. We conclude that NRF2 is a novel drug target for reversing corticosteroid resistance in COPD and other corticosteroid-resistant inflammatory diseases.
Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice
Authors: Franz Baudenbacher, Tilmann Schober, Jose Renato Pinto, Veniamin Y. Sidorov, Fredrick Hilliard, R. John Solaro, James D. Potter, Björn C. Knollmann
Journal: Journal of Clinical Investigation (2008)

In human cardiomyopathy, anatomical abnormalities such as hypertrophy and fibrosis contribute to the risk of ventricular arrhythmias and sudden death. Here we have shown that increased myofilament Ca2+ sensitivity, also a common feature in both inherited and acquired human cardiomyopathies, created arrhythmia susceptibility in mice, even in the absence of anatomical abnormalities. In mice expressing troponin T mutants that cause hypertrophic cardiomyopathy in humans, the risk of developing ventricular tachycardia was directly proportional to the degree of Ca2+ sensitization caused by the troponin T mutation. Arrhythmia susceptibility was reproduced with the Ca2+-sensitizing agent EMD 57033 and prevented by myofilament Ca2+ desensitization with blebbistatin. Ca2+ sensitization markedly changed the shape of ventricular action potentials, resulting in shorter effective refractory periods, greater beat-to-beat variability of action potential durations, and increased dispersion of ventricular conduction velocities at fast heart rates. Together these effects created an arrhythmogenic substrate. Thus, myofilament Ca2+ sensitization represents a heretofore unrecognized arrhythmia mechanism. The protective effect of blebbistatin provides what we believe to be the first direct evidence that reduction of Ca2+ sensitivity in myofilaments is antiarrhythmic and might be beneficial to individuals with hypertrophic cardiomyopathy.
Mitogen Activated Protein Kinases: Erk/jnk/p38, And The Transcription Factor Ap-1, In Addition To I-kk And NF-kB Are Dysregulated And Contribute To Excessive Il-8 Secretion In Cystic Fibrosis Epithelial Cells
Authors: A SAADANE, M BERGER
Journal: Journal of Allergy and Clinical Immunology (2008)
Recognising heart failure in elderly patients with stable chronic obstructive pulmonary disease in primary care: cross sectional diagnostic study
Authors: Frans H Rutten, Karel G M Moons, Maarten-Jan M Cramer, Diederick E Grobbee, Nicolaas P A Zuithoff, an-Willem J Lammers, Arno W Hoes
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objective</b> To determine which clinical variables provide diagnostic information in recognising heart failure in primary care patients with stable chronic obstructive pulmonary disease (COPD) and whether easily available tests provide added diagnostic information. <b>Design</b> Cross sectional diagnostic study. <b>Setting</b> 51 primary care practices. <b>Participants</b> 1186 patients aged  65 years with COPD diagnosed by their general practitioner who did not have a diagnosis of heart failure confirmed by a cardiologist. <b>Main outcome measures</b> Independent diagnostic variables for concomitant heart failure in primary care patients with stable COPD. <b>Results</b> 405 patients (34% of eligible patients) underwent a systematic diagnostic investigation, which resulted in 83 (20.5%) receiving a new diagnosis of concomitant heart failure. Independent clinical variables for concomitant heart failure were a history of ischaemic heart disease, high body mass index, laterally displaced apex beat, and raised heart rate (area under the receiver operating characteristic curve (ROC area) 0.70, 95% confidence interval 0.64 to 0.76). Addition of measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) to the reduced “clinical model” had the largest added diagnostic value, with a significant increase of the ROC area to 0.77 (0.71 to 0.83), followed by electrocardiography (0.75, 0.69 to 0.81). C reactive protein and chest radiography had limited added value. A simplified diagnostic model consisting of the four independent clinical variables plus NT-proBNP and electrocardiography was developed. <b>Conclusions</b> A limited number of items easily available from history and physical examination, with addition of NT-proBNP and electrocardiography, can help general practitioners to identify concomitant heart failure in individual patients with stable COPD.
Three-Year Trials of Personal Therapy Among Schizophrenic Patients Living With or Independent of Family, II: Effects on Adjustment of Patients
Authors: Gerard E. Hogarty, Deborah Greenwald, Richard F. Ulrich, Sander J. Kornblith, Ann Louise DiBarry, Susan Cooley, Mary Carter, Samuel Flesher
Journal: American Journal of Psychiatry (1997)

OBJECTIVE: Previous analyses of the personal and social adjustment of outpatients with schizophrenia have either relied on the assessment of unrepresentative patients who survived without relapse or used analyses that included relapse assessments, a potential confound when different rates of relapse existed among treatment conditions. The authors' goal was to conduct a study of the effects of personal therapy on outcome that was designed to take into consideration the effects of relapse. METHOD: They evaluated the effectiveness of personal therapy over 3 years after hospital discharge among 151 patients with schizophrenia or schizoaffective disorder. The patients were randomly assigned to receive personal therapy or contrasting therapies in one of two concurrent trials. One trial included patients who were living with family (N=97); the other included patients who were living independent of family (N=54). Patients were assessed at 6-month intervals over 3 years of treatment on measures of personal and social adjustment; patients who relapsed and restabilized and those who did not relapse were included. RESULTS: Personal therapy had positive effects on broad components of social adjustment (role performance) but had few differential effects on symptoms, and patients receiving personal therapy remained more anxious than patients who received family or supportive therapy. For patients who were living with family, personal therapy led to better outcomes in overall performance than did the other treatments. Although family therapy had only one positive effect on patients' social adjustment, the personal adjustment (residual symptoms) of patients who received family therapy appeared to improve more than that of patients receiving personal or supportive therapy. For patients not living with family, personal therapy was more successful than supportive therapy in improving work performance and relationships out of the home. Longitudinal effects of personal therapy on symptoms were similar to those of family and supportive therapies, particularly in the first 2 years, but personal therapy effect sizes increased over time on measures of social adjustment. CONCLUSIONS: Personal therapy has pervasive effects on the social adjustment of patients with schizophrenia that are independent of relapse prevention. Supportive therapy, with or without family intervention, produces adjustment effects that peak at 12 months after discharge and plateau thereafter. However, personal therapy, a definitive psychosocial intervention, continues to improve the social adjustment of patients in the second and third years after discharge. Brief treatment would appear to be less effective than a long-term, disorder-relevant intervention for schizophrenia. (Am J Psychiatry 1997; 154:1514–1524)
Role of iron in Trypanosoma cruzi infection of mice.
Authors: R G Lalonde, B E Holbein
Journal: Journal of Clinical Investigation (1984)

The role of iron in experimental infection of mice with Trypanosoma cruzi was investigated. B6 mice had a transient parasitemia and a transient anemia, both of maximal intensity 28 d after the inoculation of T. cruzi. There was a biphasic hypoferremic host response to infection with T. cruzi with the peak hypoferremia also occurring 28 d after inoculation of the parasite. The mortality rate from infection was increased from 23% in phosphate-buffered saline-treated B6 mice to 50% in a group of B6 mice receiving iron-dextran (P less than or equal to 0.025), whereas depletion of iron stores with the iron chelator desferrioxamine B and an iron-deficient diet provided complete protection of B6 mice (P less than or equal to 0.05). The mortality rate in the highly susceptible C3H strain was reduced from 100% in the control group to 45% (P less than or equal to 0.025) in the iron-depleted group. The tissue iron stores were altered in mice receiving either iron-dextran or desferrioxamine B and an iron-deficient diet. In vitro, T. cruzi was shown to require both a heme and a nonheme iron source for an optimal growth rate. The effects of iron excess or depletion on the outcome of infection with T. cruzi correlated both with the growth requirements of the parasite for iron and with the availability of intracellular iron. Thus, it was suggested that the hypoferremic response, by sequestering iron within intracellular stores, potentially enhanced the pathogenicity of the intracellular parasites. Furthermore, the in vivo effects of iron excess and depletion correlated with an effect of iron on the growth rate and pathogenicity of the parasite.
The effect of OSAS on sick leave and work disability
Authors: B. Sivertsen, S. Øverland, N. Glozier, B. Bjorvatn, J. G. Mæland, A. Mykletun
Journal: European Respiratory Journal (2008)

The objective of the present study was to examine the independent contribution of symptoms of obstructive sleep apnoea syndrome (OSAS) to long-term sick leave and permanent work disability. Using a historical cohort design with 4 yrs of follow-up, information on sick leave and disability benefit recipiency were merged with health information from the Hordaland Health Study, carried out in western Norway during 1997–1999. Persons aged 40–45 yrs (n = 7,028) were assessed for self-reported symptoms of OSAS (snoring, breathing cessations and daytime sleepiness), body mass index, somatic conditions and other potential confounders. The outcomes, cumulative sick leave of ≥8 weeks and permanent work disability, were identified in records from the National Insurance Administration. After excluding participants with work disability at baseline, symptoms of OSAS were found to be a significant predictor of both subsequent long-term sick leave and permanent work disability. These effects remained significant after adjustment for a range of possible confounding factors. Daytime sleepiness showed the greatest explanatory power, followed by breathing cessations and snoring. It is concluded that self-reported symptoms of obstructive sleep apnoea syndrome are an independent risk factor for subsequent long-term sick leave and permanent work disability. These findings need to be replicated using objective measures of obstructive sleep apnoea syndrome.
Essays in Medical Biochemistry
Authors: H Lehmann
Journal: BMJ (1975)

Precision oncology is predicated upon the ability to detect specific actionable genomic alterations and to monitor their adaptive evolution during treatment to counter resistance. Because of spatial and temporal heterogeneity and comorbidities associated with obtaining tumor tissues, especially in the case of metastatic disease, traditional methods for tumor sampling are impractical for this application. Known to be present in the blood of cancer patients for decades, cell-free DNA (cfDNA) is beginning to inform on tumor genetics, tumor burden, and mechanisms of progression and drug resistance. This substrate is amenable for inexpensive noninvasive testing and thus presents a viable approach to serial sampling for screening and monitoring tumor progression. The fragmentation, low yield, and variable admixture of normal DNA present formidable technical challenges for realization of this potential. This review summarizes the history of cfDNA discovery, its biological properties, and explores emerging technologies for clinically relevant sequence-based analysis of cfDNA in cancer patients. Molecular barcoding (or Unique Molecular Identifier, UMI)-based methods currently appear to offer an optimal balance between sensitivity, flexibility, and cost and constitute a promising approach for clinically relevant assays for near real-time monitoring of treatment-induced mutational adaptations to guide evidence-based precision oncology. Mol Cancer Res; 14(10); 898–908. ©2016 AACR.
Airway Inflammation and Bronchial Bacterial Colonization in Chronic Obstructive Pulmonary Disease
Authors: Sanjay Sethi, Jane Maloney, Lori Grove, Catherine Wrona, Charles S. Berenson
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Inflammation is now recognized as an integral part of the pathogenesis of chronic obstructive pulmonary disease (COPD). In contrast to the sterile airways of normal lungs, bacterial pathogens are often isolated from the airways in stable COPD. This "colonization" of the tracheobronchial tree, currently believed to be innocuous, could serve as an inflammatory stimulus, independent of current tobacco smoke exposure.To test the hypothesis that bacterial colonization is associated with airway inflammation in stable COPD.Bronchoscopy with bronchoalveolar lavage (BAL) was performed in three groups of subjects: 26 ex-smokers with stable COPD (COPD), 20 ex-smokers without COPD (ex-smokers), and 15 healthy nonsmokers (nonsmokers). Quantitative bacterial cultures, cell counts, chemokine, cytokine, proteinase/antiproteinase, and endotoxin levels in the BAL fluid were compared.Potentially pathogenic bacteria were recovered at > or = 100 cfu/ml in 34.6% of COPD, 0% of ex-smokers, and in 6.7% of nonsmokers (p = 0.003). All values are expressed as median (interquartile range). Subjects with colonized COPD had significantly greater relative (12.0 [28.4] vs. 3.0 [7.8]%, p = 0.03) and absolute (4.98 [5.26] x 10(4)/ml vs. 3.04 [2.82] x 10(4)/ml, p = 0.02) neutrophil counts, interleukin 8 (33.8 [189.8] vs. 16.9 [20.1] pg/ml, p = 0.005), active matrix metalloproteinase-9 (2.16 [4.30] vs. 0.84 [0.99] U/ml, p = 0.03), and endotoxin (36.0 [72.6] vs. 3.55 [7.17] mEU/ml, p = 0.004) levels in the BAL than the subjects with noncolonized COPD. These inflammatory constituents of BAL were also significantly elevated in subjects with colonized COPD when compared with ex-smokers and nonsmokers.Bacterial colonization is associated with neutrophilic airway lumen inflammation in ex-smokers with COPD and could contribute to progression of airway disease in COPD.
Osteopontin as an Adjunct to CA125 in Detecting Recurrent Ovarian Cancer
Authors: John O. Schorge, Richard D. Drake, Hang Lee, Steven J. Skates, Ramababu Rajanbabu, David S. Miller, Jae-Hoon Kim, Daniel W. Cramer, Ross S. Berkowitz, Samuel C. Mok
Journal: Clinical Cancer Research (2004)

Abstract Purpose: CA125 is currently the only tumor marker to have a validated role in the postoperative monitoring of ovarian cancer. Osteopontin (OPN) is a putative plasma biomarker that was recently identified using high-throughput cDNA microarray technology. The purpose of this study was to test the hypothesis that OPN is a clinically useful adjunct to CA125 in detecting recurrent ovarian cancer. Experimental Design: Thirty-eight ovarian cancer patients had a single pretreatment blood sample and 200 postoperative specimens were prospectively collected during chemotherapy and follow-up. OPN measurements were performed using an enzyme-linked immunoassay, and CA125 levels were concurrently obtained. Wilcoxon’s signed rank-sum test was used to perform paired comparisons between pretreatment and postoperative OPN and CA125 measurements. Longitudinal mixed effects polynomial models were used to determine whether OPN and CA125 levels correlated with the development of recurrent ovarian cancer. Results: The median pretreatment OPN level was 178 ng/ml (range, 12–3468) and the median CA125 measurement was 812 units/ml (range, 12–81,500). There was a trend for OPN levels to decline after treatment was initiated (P = 0.07), but decreasing CA125 measurements were more consistently observed (P = 0.0009). The quadratic functional trends of OPN and CA125 were each highly significant (P &amp;lt; 0.0001). Although inferior to CA125 in predicting clinical response to therapy, OPN rose earlier in 90% (95% confidence interval, 56–100%) of the patients developing recurrent disease (median lead time, 3 months). Conclusions: OPN may be a clinically useful adjunct to CA125 in detecting recurrent ovarian cancer.
Rituximab modulates the expression of IL-22 in the salivary glands of patients with primary Sjogren's syndrome
Authors: Francesco Ciccia, AnnaRita Giardina, Aroldo Rizzo, Giuliana Guggino, Paola Cipriani, Francesco Carubbi, Roberto Giacomelli, Giovanni Triolo
Journal: Annals of the Rheumatic Diseases (2012)

We have recently demonstrated that interleukin (IL)-22, mainly produced by T-helper 17 effector cells, natural killer (NK)p44+NK cells and epithelial cells, may be potentially involved in the pathogenesis of primary Sjogren's syndrome (pSS).1 The IL-22/IL-22R pathway is known to play a role in the emergence of T and B-cell lymphoma2 ,3 and pSS is considered a risk factor for the development of lymphoma.4

Rituximab, which has historically been used for the treatment of B-cell lymphoma,5 has also been considered to be effective in the therapy of pSS.6

Ten consecutive patients with pSS (eight women and two men, with a mean duration of disease of 48±18 months), diagnosed according to the American–European Consensus Group criteria for pSS,7 who were treated with two courses of intravenous infusions of 1000 mg rituximab (Roche, Woerden, The Netherlands) at days 1 and 15, at baseline and then after 6 months, were considered for this study. After 48 weeks the patients again underwent salivary gland biopsy. The demographic, clinical and histological characteristics of …
Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: a meta-analysis
Authors: D. Nitsch, M. Grams, Y. Sang, C. Black, M. Cirillo, O. Djurdjev, K. Iseki, S. K. Jassal, H. Kimm, F. Kronenberg, C. M. Oien, A. S. Levey, A. Levin, M. Woodward, B. R. Hemmelgarn
Journal: BMJ (2013)

To assess for the presence of a sex interaction in the associations of estimated glomerular filtration rate and albuminuria with all-cause mortality, cardiovascular mortality, and end stage renal disease.Random effects meta-analysis using pooled individual participant data.46 cohorts from Europe, North and South America, Asia, and Australasia.2,051,158 participants (54% women) from general population cohorts (n=1,861,052), high risk cohorts (n=151,494), and chronic kidney disease cohorts (n=38,612). Eligible cohorts (except chronic kidney disease cohorts) had at least 1000 participants, outcomes of either mortality or end stage renal disease of ≥ 50 events, and baseline measurements of estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation (mL/min/1.73 m(2)) and urinary albumin-creatinine ratio (mg/g).Risks of all-cause mortality and cardiovascular mortality were higher in men at all levels of estimated glomerular filtration rate and albumin-creatinine ratio. While higher risk was associated with lower estimated glomerular filtration rate and higher albumin-creatinine ratio in both sexes, the slope of the risk relationship for all-cause mortality and for cardiovascular mortality were steeper in women than in men. Compared with an estimated glomerular filtration rate of 95, the adjusted hazard ratio for all-cause mortality at estimated glomerular filtration rate 45 was 1.32 (95% CI 1.08 to 1.61) in women and 1.22 (1.00 to 1.48) in men (P(interaction)<0.01). Compared with a urinary albumin-creatinine ratio of 5, the adjusted hazard ratio for all-cause mortality at urinary albumin-creatinine ratio 30 was 1.69 (1.54 to 1.84) in women and 1.43 (1.31 to 1.57) in men (P(interaction)<0.01). Conversely, there was no evidence of a sex difference in associations of estimated glomerular filtration rate and urinary albumin-creatinine ratio with end stage renal disease risk.Both sexes face increased risk of all-cause mortality, cardiovascular mortality, and end stage renal disease with lower estimated glomerular filtration rates and higher albuminuria. These findings were robust across a large global consortium.