tbuckley/cabot-search huggingface dataset:
Prospective evaluation of local control and late effects of conformal radiation therapy in children, adolescents, and young adults with high-grade glioma
Authors: Tamara Z. Vern-Gross, Jane E. Schreiber, Alberto Broniscer, Shengjie Wu, Xiaoping Xiong, Thomas E. Merchant
Journal: Neuro-Oncology (2014)

A phase II trial of conformal radiotherapy (CRT) for pediatric high-grade glioma (HGG) was performed to evaluate disease control and late effects. Between July 1997 and January 2003, 34 pediatric patients (median age, 13.2 ± 6.7 years) with HGG were enrolled on an International Commission on Radiation Units and Measurements Report 50-compliant prospective trial using CRT with a 2 cm clinical target volume margin. Baseline and serial evaluations were performed to assess functional outcomes. Median follow-up for the entire group was 18 months (range, 2–134 months). Twenty (58.8%) patients developed local progression, and 6 (17.6%) patients developed distant progression. Progression-free and overall survival at 10 years were 18.8% ± 6.9% and 16.8% ± 6.5%, respectively. At baseline, 40% of patients evaluated for intelligence quotient (IQ) scored below 85. Measures of cognitive function obtained during the first 12 months fit a mixed model with a quadratic function. The relationship between IQ and time was -1.1883 points/month for the linear term and 0.07728 points/month for the quadratic term (P = .0454). IQ decreased between baseline and 6 months and then increased slightly through 12 months. The opposite was found for (all P values of the quadratic term) activities of daily living (P = .0155), socialization (P = .0049), and the composite score (P = .0257) of adaptive behavior. CRT using a 2 cm clinical target volume margin in pediatric HGG demonstrated tumor control comparable to conventional radiation therapy. Disrupted cognitive and adaptive behavioral functioning were present at baseline and throughout the course of disease.
Drug survival on TNF inhibitors: 2003–2004 data from Italian National Register (GISEA Register)
Authors: Florenzo Iannone, Gianfranco Ferraccioli, Elisa Gremese, Giovanni Lapadula
Journal: Annals of the Rheumatic Diseases (2013)

We read with interest the findings of the paper by Neovius et al 1 recently published on Annals of the Rheumatic Diseases who retrospectively studied the drug survival on tumour necrosis factor (TNF)-α blockers in patients with rheumatoid arthritis (RA) in real-life settings. The primary endpoint of their analysis was to assess the drug discontinuation rates in RA patients starting a first ever TNF-α inhibitor and to compare between-group survival rates for the historical anti-TNF-α drugs, namely adalimumab, etanercept and infliximab, during 5 years of follow-up. Additionally, they also evaluated the discontinuation rates of each anti-TNF-α drug across calendar period. They selected patients starting the treatment since 2003, …
High diagnostic accuracy of NT-proBNP for cardiac origin of pleural effusions
Authors: M. Kolditz
Journal: European Respiratory Journal (2006)

A prospective study was performed to evaluate the diagnostic accuracy of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) levels, measured simultaneously in serum and pleural fluid, in identifying pleural effusions due to heart failure. Pleural fluid and serum samples from all patients presenting for thoracentesis between April 2004 and May 2005 were simultaneously collected. The discriminative properties of NT-proBNP levels in identifying pleural effusions due to heart failure were determined by receiver operating characteristic curve analysis and compared to the diagnostic value of finding a transudate by Light9s criteria. Ninety-three patients were evaluated, 27% with cardiac effusion and 73% with exudative effusions of various cause. Levels of NT-proBNP in pleural fluid and serum correlated closely. Serum and pleural fluid NT-proBNP levels were significantly elevated in patients with cardiac effusion. With a cut-off value of 4,000 ng·L<sup>−1</sup>, NT-proBNP levels in pleural fluid and serum displayed comparably high diagnostic accuracies of 92 and 91%, respectively. All patients misclassified by Light9s criteria were correctly identified by measuring NT-proBNP levels. N-terminal-pro-B-type natriuretic peptide levels in either pleural fluid or serum showed a high diagnostic accuracy compared to traditional criteria. Thus measuring N-terminal-pro-B-type natriuretic peptide is a valuable additional diagnostic tool for the detection or exclusion of cardiac origin of pleural effusions.
Synergistic epigenetic reactivation of estrogen receptor-α (ERα) by combined green tea polyphenol and histone deacetylase inhibitor in ERα-negative breast cancer cells
Authors: Yuanyuan Li, Yih-Ying Yuan, Syed M Meeran, Trygve O Tollefsbol
Journal: Molecular Cancer (2010)

Abstract Background The status of estrogen receptor-α (ERα) is critical to the clinical prognosis and therapeutic approach in breast cancer. ERα-negative breast cancer is clinically aggressive and has a poor prognosis because of the lack of hormone target-directed therapies. Previous studies have shown that epigenetic regulation plays a major role in ERα silencing in human breast cancer cells. Dietary green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), is believed to be an anticancer agent in part through its regulation of epigenetic processes. Results In our current studies, we found that EGCG can reactivate ERα expression in ERα-negative MDA-MB-231 breast cancer cells. Combination studies using EGCG with the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), revealed a synergistic effect of reactivation of ERα expression in ERα-negative breast cancer cells. Reactivation of ERα expression by EGCG and TSA treatment was found to sensitize ERα-dependent cellular responses to activator 17β-estradiol (E 2 ) and antagonist tamoxifen in ERα-negative breast cancer cells. We also found that EGCG can lead to remodeling of the chromatin structure of the ERα promoter by altering histone acetylation and methylation status thereby resulting in ERα reactivation. A decreased binding of the transcription repressor complex, Rb/p130-E2F4/5-HDAC1-SUV39H1-DNMT1, in the regulatory region of the ERα promoter also contributes to ERα transcriptional activation through treatment with EGCG and/or TSA. Conclusions Collectively, these studies show that green tea EGCG can restore ERα expression by regulating epigenetic mechanisms, and this effect is enhanced when combined with an HDAC inhibitor. This study will facilitate more effective uses of combination approaches in breast cancer therapy and will help to explore more effective chemotherapeutic strategies toward hormone-resistant breast cancer.
Acquisition and eradication of P. aeruginosa in young children with cystic fibrosis
Authors: T. A. Douglas, S. Brennan, S. Gard, L. Berry, C. Gangell, S. M. Stick, B. S. Clements, P. D. Sly
Journal: European Respiratory Journal (2008)

When do infants and young children with cystic fibrosis acquire infection with Pseudomonas aeruginosa ? Can this be eradicated when first detected? Children &lt;6 yrs of age participated in an annual bronchoalveolar lavage (BAL)-based microbiological surveillance programme in Perth, Australia. When P. aeruginosa was detected, an eradication programme using combination treatment with i.v. , oral and nebulised antibiotics was undertaken. Repeat BAL was performed 3 months following treatment, to assess eradication success. P. aeruginosa was detected in 33 (28.4%) children; median (range) age at detection was 30.5 (3.3–71.4) months. P. aeruginosa was mucoid at detection in six (18.2%) out of 33 patients and associated with respiratory symptoms in 16 (48.5%) out of 33 children. In total, 26 children underwent eradication therapy, with P. aeruginosa eradicated in 20 (77%) out of 26 following one eradication cycle and in three (total 88%) additional children following a second cycle. Eradication was associated with a significant decrease in neutrophil elastase and interleukin-1β in BAL fluid 12 months post eradication. Eradication of Pseudomonas aeruginosa infection is achievable in young children with cystic fibrosis for up to 5 yrs using combination i.v. , oral and nebulised antibiotic therapy and is associated with reduced pulmonary inflammation 12 months post eradication.
Acute Antiinflammatory Properties of Statins Involve Peroxisome Proliferator–Activated Receptor-α via Inhibition of the Protein Kinase C Signaling Pathway
Authors: Réjane Paumelle, Christophe Blanquart, Olivier Briand, Olivier Barbier, Christian Duhem, Gaëtane Woerly, Frédéric Percevault, Jean-Charles Fruchart, David Dombrowicz, Corine Glineur, Bart Staels
Journal: Circulation Research (2006)

Statins are inhibitors of 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase used in the prevention of cardiovascular disease (CVD). In addition to their cholesterol-lowering activities, statins exert pleiotropic antiinflammatory effects, which might contribute to their beneficial effects not only on CVD but also on lipid-unrelated immune and inflammatory diseases, such as rheumatoid arthritis, asthma, stroke, and transplant rejection. However, the molecular mechanisms involved in these antiinflammatory properties of statins are unresolved. Here we show that the peroxisome proliferator–activated receptor (PPAR) α mediates antiinflammatory effects of simvastatin in vivo in models of acute inflammation. The inhibitory effects of statins on lipopolysaccharide-induced inflammatory response genes were abolished in PPARα-deficient macrophages and neutrophils. Moreover, simvastatin inhibited PPARα phosphorylation by lipopolysaccharide-activated protein kinase C (PKC) α. A constitutive active form of PKCα inhibited nuclear factor κB transrepression by PPARα whereas simvastatin enhanced transrepression activity of wild-type PPARα, but not of PPARα mutated in its PKC phosphorylation sites. These data indicate that the acute antiinflammatory effect of simvastatin occurs via PPARα by a mechanism involving inhibition of PKCα inactivation of PPARα transrepression activity.
Chimeric antigen receptor for adoptive immunotherapy of cancer: latest research and future prospects
Authors: Huan Shi, Meili Sun, Lin Liu, Zhehai Wang
Journal: Molecular Cancer (2014)

Chimeric antigen receptors (CARs) are recombinant receptors that combine the specificity of an antigen-specific antibody with the T-cell’s activating functions. Initial clinical trials of genetically engineered CAR T cells have significantly raised the profile of T cell therapy, and great efforts have been made to improve this approach. In this review, we provide a structural overview of the development of CAR technology and highlight areas that require further refinement. We also discuss critical issues related to CAR therapy, including the optimization of CAR T cells, the route of administration, CAR toxicity and the blocking of inhibitory molecules.
Endothelin in acute exacerbations of COPD
Authors: M SOFIA
Journal: Thorax (2001)

seem to be specific to PCH, demonstrating the usefulness of HRCT scanning for diagnosis of this disease.Other previously reported CT findings of the disease include increased soft tissue density of the mediastinum 1 2 and mediastinal and hilar lymph adenopathies, 7 but such findings were absent in our case.Possible explanations for the stable condition of our case over a long period are either that it was a chance discovery of an early phase of the disease by HRCT scanning or that PCH has separate subtypes with diVering speeds of progression.Wider use of HRCT scanning and more extensive understanding of PCH would resolve this issue in the future.
Thromboembolism in Patients With Advanced Gastroesophageal Cancer Treated With Anthracycline, Platinum, and Fluoropyrimidine Combination Chemotherapy: A Report From the UK National Cancer Research Institute Upper Gastrointestinal Clinical Studies Group
Authors: Naureen Starling, Sheela Rao, David Cunningham, Timothy Iveson, Marianne Nicolson, Fareeda Coxon, Gary Middleton, Francis Daniel, Jacqueline Oates, Andrew Richard Norman
Journal: Journal of Clinical Oncology (2009)

Data concerning the prevalence of and outcomes related to thromboembolic events (TEs) in patients with advanced gastroesophageal cancer who are undergoing chemotherapy are limited.This was a prospective, exploratory analysis of TEs in a randomized, controlled trial of 964 patients recruited between 2000 and 2005 and treated with epirubicin/platinum/fluoropyrimidine combination chemotherapy for advanced/locally advanced gastroesophageal cancer. Regimens were epirubicin (E), cisplatin (C), fluorouracil (F; ECF); E, C, capecitabine (X; ECX); E, F, oxaliplatin (O; EOF); and EOX. Continuously infused F was administered via a central venous access device (CVAD) with 1 mg of warfarin for thromboprophylaxis. The principal outcome was the incidence of TEs (venous and arterial) in the whole treated patient cohort, according to chemotherapy, associated with CVADs and TE-related prognoses.The incidences of any, of venous, and of arterial TEs among 964 treated patients were 12.1% (95% CI, 10.7 to 14.3), 10.1% (95% CI, 8.3 to 12.3), and 2.2% (95% CI, 1.4 to 3.4) respectively. There were fewer TEs in the O compared with the cisplatin groups (EOF/EOX v ECF/ECX: 7.6% v 15.1%; P = .0003). C was identified as a risk factor for TE in multivariate analysis (hazard ratio [HR], 0.51; 95% CI, 0.34 to 0.76; P = .001). There was no difference in the incidence of TEs for the F group compared with the capecitabine groups. The incidence of CVAD-related thrombosis was 7.0% (ECF/EOF arms). Overall survival was worse for patients who experienced TEs versus no TEs (median survival, 7.4 v 10.5 months; HR, 0.8; 95% CI, 0.64 to 0.99; P = .043).This analysis has prospectively quantified the incidence/pattern of TEs among patients with advanced gastroesophageal cancer who were treated with four triplet regimens, has demonstrated a differential thrombogenic effect according to platinum use, and has noted a poorer outcome associated with TE during treatment. Chemotherapy-related TE should contribute to the risk/benefit assessment of treatment.
Asthma survey items as predictors of respiratory problems in children 2 yrs later: a longitudinal study
Authors: P.k. Pattemore, F.c. Lampe, S Smith, J.b Clough, S.t Holgate, S.l Johnston
Journal: European Respiratory Journal (1999)

The study compared the ability of characteristics defined by an asthma survey (wheeze versus cough and asthma diagnosis versus no diagnosis) to predict later respiratory problems in a cohort of 108 schoolchildren who had reported either recent wheeze or recurrent cough in a 1987 asthma survey. The children recorded daily respiratory symptoms and peak flow from April 1989 until May 1990. The frequency and severity of lower respiratory symptom episodes and peak flow dips were compared in the wheeze and cough groups and in the diagnosed versus nondiagnosed children. The independent effects of initial wheeze, atopy, diagnosis and bronchial hyperresponsiveness (BHR) on the longitudinal outcome measures were assessed using multiple linear regression. Children with initial wheeze had more chronic symptoms and peak flow variability than those with cough alone, but wheeze had only a weak effect on frequency and severity of acute lower respiratory episodes. Children with both wheeze and atopy had more acute symptomatic episodes and more chronic symptoms than did the other children. Children with diagnosed asthma (versus no diagnosis) had significantly more frequent and severe lower respiratory exacerbations, more days symptomatic and greater peak flow variability. The predictive effects of diagnosis were independent of (and stronger than the effects of) wheeze, atopy and BHR, or combinations of these variables. The results suggest that among children who report respiratory symptoms, survey-reported wheeze on its own is a weaker marker of significant respiratory disease than is a doctor9s diagnosis of asthma.
CaMKII-Dependent Diastolic SR Ca <sup>2+</sup> Leak and Elevated Diastolic Ca <sup>2+</sup> Levels in Right Atrial Myocardium of Patients With Atrial Fibrillation
Authors: Stefan Neef, Nataliya Dybkova, Samuel Sossalla, Katharina R. Ort, Nina Fluschnik, Kay Neumann, Ralf Seipelt, Friedrich A. Schöndube, Gerd Hasenfuss, Lars S. Maier
Journal: Circulation Research (2010)

Although research suggests that diastolic Ca(2+) levels might be increased in atrial fibrillation (AF), this hypothesis has never been tested. Diastolic Ca(2+) leak from the sarcoplasmic reticulum (SR) might increase diastolic Ca(2+) levels and play a role in triggering or maintaining AF by transient inward currents through Na(+)/Ca(2+) exchange. In ventricular myocardium, ryanodine receptor type 2 (RyR2) phosphorylation by Ca(2+)/calmodulin-dependent protein kinase (CaMK)II is emerging as an important mechanism for SR Ca(2+) leak.We tested the hypothesis that CaMKII-dependent diastolic SR Ca(2+) leak and elevated diastolic Ca(2+) levels occurs in atrial myocardium of patients with AF.We used isolated human right atrial myocytes from patients with AF versus sinus rhythm and found CaMKII expression to be increased by 40+/-14% (P<0.05), as well as CaMKII phosphorylation by 33+/-12% (P<0.05). This was accompanied by a significantly increased RyR2 phosphorylation at the CaMKII site (Ser2814) by 110+/-53%. Furthermore, cytosolic Ca(2+) levels were elevated during diastole (229+/-20 versus 164+/-8 nmol/L, P<0.05). Most likely, this resulted from an increased SR Ca(2+) leak in AF (P<0.05), which was not attributable to higher SR Ca(2+) load. Tetracaine experiments confirmed that SR Ca(2+) leak through RyR2 leads to the elevated diastolic Ca(2+) level. CaMKII inhibition normalized SR Ca(2+) leak and cytosolic Ca(2+) levels without changes in L-type Ca(2+) current.Increased CaMKII-dependent phosphorylation of RyR2 leads to increased SR Ca(2+) leak in human AF, causing elevated cytosolic Ca(2+) levels, thereby providing a potential arrhythmogenic substrate that could trigger or maintain AF.
In vivo transfer of nitric oxide between a plasma protein-bound reservoir and low molecular weight thiols.
Authors: J S Scharfstein, J F Keaney, A Slivka, G N Welch, J A Vita, J S Stamler, J Loscalzo
Journal: Journal of Clinical Investigation (1994)

Plasma albumin reacts with nitric oxide (NO) to form the bioactive adduct, S-nitroso-albumin (S-NO-albumin). The limited intracellular access of S-NO-albumin suggests the need for a vascular transfer mechanism of NO from a large plasma S-NO-albumin pool to effect biologic function. To study the role of low molecular weight (LMW) thiols in NO transfer in vivo, we administered intravenous S-NO-albumin (1-300 nmol/kg) to rabbits before and after an intravenous infusion of L-cysteine or N-acetyl-L-cysteine. S-NO-albumin produced dose-dependent hypotension that was significantly augmented by prior infusion of either LMW thiol. LMW thiol infusion significantly accelerated the rate of onset and reduced the duration of action of the hypotension induced by S-NO-albumin. The hemodynamic effects of S-NO-albumin after pretreatment with LMW thiols were mimicked by administration of the corresponding LMW S-nitrosothiol. The transfer of NO from albumin to L-cysteine was directly measured in rabbit plasma using a novel technique that couples high performance liquid chromatography to electrochemical detection. These data demonstrate that NO exchange between plasma protein thiol-bound NO and available LMW thiol pools (transnitrosation) occurs in vivo.
Downregulation of SPARC Expression Is Mediated by Nitric Oxide in Rat Mesangial Cells and during Endotoxemia in
Authors: SEBASTIAN WALPEN, KARL-FRIEDRICH BECK, WOLFGANG EBERHARDT, MARTINA APEL, PRABAL K. CHATTERJEE, GILLIAN M. H. WRAY, CHRISTOPH THIEMERMANN, JOSEF PFEILSCHIFTER
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Nitric oxide (NO) has been implicated in several forms of glomerulonephritis. In this study, a low stringency reversed transcription/PCR protocol was used to evaluate the action of NO on the mRNA expression pattern in rat mesangial cells (MC). To mimic the state of glomerular inflammation, MC were stimulated by exposure to the cytokines interleukin-1β and tumor necrosis factor-α into producing high levels of NO via expression of inducible nitric oxide synthase (NOS). To detect NO-mediated effects, the resulting expression pattern was compared to that of MC stimulated by the cytokines in the presence of the NOS inhibitor N G -monomethyl-L-arginine (L-NMMA). Computer analysis of a differentially expressed cDNA fragment resulted in a 100% homology to the recently characterized mRNA of SPARC (secreted protein acidic and rich in cysteine). Further characterization of SPARC regulation revealed a cytokine- and cAMP-dependent decrease in SPARC mRNA and protein levels. Blocking NO formation by L-NMMA reversed the effects of cytokines and cAMP on SPARC expression, suggesting an NO-mediated mechanism. The NO donors S -nitroso- N -acetyl-penicillamine and diethyl-enetriamine/NO further reduced SPARC expression in cytokine-treated MC as well as in controls. Moreover, downregulation of SPARC mRNA and protein expression in whole kidneys obtained from rats treated with endotoxin was observed. This downregulation of SPARC was reversed by treatment with L- N 6 -l (iminoethyl) lysine dihydrochloride, a potent and highly selective inhibitor of inducible NOS. These data characterize SPARC as an NO-regulated gene. This observation may be important in the context of tissue remodeling in chronic inflammatory kidney diseases.
Changes in cytosolic Ca2+ associated with von Willebrand factor release in human endothelial cells exposed to histamine. Study of microcarrier cell monolayers using the fluorescent probe indo-1.
Authors: K K Hamilton, P J Sims
Journal: Journal of Clinical Investigation (1987)

A method for measuring fluorescence in anchored monolayers of human endothelial cells is described and used to demonstrate changes in the cytosolic free-calcium concentration ([Ca2+]c) in these cells exposed to histamine and thrombin; some endothelial responses to both agonists (e.g., mitogenesis) have been suggested to be Ca2+-mediated. Umbilical vein endothelial cells were cultured on microcarriers and loaded with the Ca2+ indicator, indo-1. Enzymatic cell detachment was avoided by monitoring the indo-1 fluorescence ratio (400/480 nm) of a stirred suspension of cell-covered microcarriers. Basal [Ca2+]c was estimated to be 70-80 nM. Thrombin induced a transient dose-dependent increase in [Ca2+]c, which was active-site dependent. Histamine stimulated a dose-dependent increase in [Ca2+]c, which was reversed by removal of histamine and inhibited competitively by the H1-receptor antagonist pyrilamine, but not by the H2-receptor antagonist cimetidine. Furthermore, histamine induced a dose-dependent secretion of von Willebrand factor, which paralleled the rise in [Ca2+]c and was similarly blocked by the H1-receptor antagonist, and which may contribute to platelet deposition at sites of inflammation.