tbuckley/cabot-search huggingface dataset:
Long-Term Results of the AIEOP-ALL-95 Trial for Childhood Acute Lymphoblastic Leukemia: Insight on the Prognostic Value of DNA Index in the Framework of Berlin-Frankfurt-Muenster–Based Chemotherapy
Authors: Maurizio Aricò, Maria Grazia Valsecchi, Carmelo Rizzari, Elena Barisone, Andrea Biondi, Fiorina Casale, Franco Locatelli, Luca Lo Nigro, Matteo Luciani, Chiara Messina, Concetta Micalizzi, Rosanna Parasole, Andrea Pession, Nicola Santoro, Anna Maria Testi, Daniela Silvestri, Giuseppe Basso, Giuseppe Masera, Valentino Conter
Journal: Journal of Clinical Oncology (2008)

Between May 1995 and August 2000 the Associazione Italiana di Ematologia Oncologia Pediatrica conducted the ALL-95 study for risk-directed, Berlin-Frankfurt-Muenster (BFM) -oriented therapy of childhood acute lymphoblastic leukemia, aimed at exploring treatment reduction in standard-risk patients (SR) and intensification during continuation therapy in intermediate-risk patients (IR) as randomized questions and treatment intensification in high-risk patients (HR). The prognostic value of DNA index was explored in this setting.A total of 1,744 patients were enrolled (115, SR; 1,385, IR; and 244, HR). SR patients (DNA index >/= 1.16 and < 1.60; age, 1 to 5 years; and WBC < 20,000, non-T-immunophenotype, with no high-risk features) received a reduced induction therapy (no anthracyclines); IR patients were randomly assigned to receive or not receive vincristine and dexamethasone pulses during maintenance; HR therapy was based on a conventional BFM schedule intensified with three chemotherapy blocks followed by a double reinduction phase.The event-free survival and overall survival probabilities at 10 years for the entire group were 72.5% (SE, 1.3) and 83.6% (SE, 0.9); 85.0% (SE, 3.4) and 95.5% (SE, 2.0) in SR, 75.1% (SE, 1.5) and 87.5% (SE, 0.9) in IR, and 51.0% (SE, 3.2) and 57.2% (SE, 3.3) in HR patients, respectively. Patients with a favorable DNA index had superior EFS in both IR (83.8% [2.7%] v 73.9% [1.7%]) and in HR (67.8% [9.4%] and 49.6% [3.5%]). Of the six patients with DNA index less than 0.8, only one remained in remission.Favorable DNA index was associated with a better prognosis in IR and HR patients defined by presenting clinical criteria and treatment with a BFM-oriented chemotherapy.
Physician Cost Profiling — Reliability and Risk of Misclassification
Authors: John L. Adams, Ateev Mehrotra, J. William Thomas, Elizabeth A. McGlynn
Journal: New England Journal of Medicine (2010)

Insurance products with incentives for patients to choose physicians classified as offering lower-cost care on the basis of cost-profiling tools are increasingly common. However, no rigorous evaluation has been undertaken to determine whether these tools can accurately distinguish higher-cost physicians from lower-cost physicians.
5 versus 14 days of prednisone for acute COPD exacerbations
Authors: Laura J Quint
Journal: Thorax (2013)

CLUB versus 14 days of prednisone for acute COPD exacerbationsIn this multicentre, double-blind, randomised control trial, a shorter 5-day course of glucocorticoids was compared with a 14-day course to assess non-inferiority.Patients received an initial dose of IV methylprednisone, then 4 days of oral prednisone, followed by further prednisone or a placebo.They all received antibiotics and inhaled corticosteroids and bronchodilators.No differences were seen in the primary endpoint of time to next exacerbation within the follow-up period of 6 months.Similarly, there were no differences in many of the secondary endpoints, including overall mortality, requirement for mechanical ventilation and new or worsening hypertension or hyperglycaemia.Importantly, no difference was seen in incidence of side effects of steroids despite a reduced cumulative dose of over 70% in the short-term group.The benefit gained from steroid treatment in acute exacerbations peaks within 5 days.This study confirms that further steroids seem neither to do more harm nor more good in the following 180 days.It appears that a short course of oral prednisone is as good for treating exacerbations; however, more research is needed to show that it also has benefits in the long term.At the very least, shorter courses are cheaper and reduce the polypharmacy burden on these patients.
Novel Dithiolethione-Modified Nonsteroidal Anti-Inflammatory Drugs in Human Hepatoma HepG2 and Colon LS180 Cells
Authors: Sara E. Bass, Pawel Sienkiewicz, Christopher J. MacDonald, Robert Y.S. Cheng, Anna Sparatore, Piero Del Soldato, David D. Roberts, Terry W. Moody, David A. Wink, Grace Chao Yeh
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Nonsteroidal anti-inflammatory drugs (NSAID) are promising chemopreventive agents against colon and other cancers. However, the molecular basis mediated by NSAIDs for chemoprevention has not been fully elucidated. Environmental carcinogens induce DNA mutation and cellular transformation; therefore, we examined the effect of NSAIDs on carcinogenesis mediated by the aryl hydrocarbon receptor signaling pathway. In this study, we investigated the activities of a new class of NSAIDs containing dithiolethione moieties (S-NSAID) on both arms of carcinogenesis. Experimental Design: We investigated the effects of the S-NSAIDs, S-diclofenac and S-sulindac, on carcinogen activation and detoxification mechanisms in human hepatoma HepG2 and human colonic adenocarcinoma LS180 cells. Results: We found that S-diclofenac and S-sulindac inhibited the activity and expression of the carcinogen activating enzymes, cytochromes P-450 (CYP) CYP1A1, CYP1B1, and CYP1A2. Inhibition was mediated by transcriptional regulation of the aryl hydrocarbon receptor (AhR) pathway. The S-NSAIDs down-regulated carcinogen-induced expression of CYP1A1 heterogeneous nuclear RNA, a measure of transcription rate. Both compounds blocked carcinogen-activated AhR from binding to the xenobiotic responsive element as shown by chromatin immunoprecipitation. S-diclofenac and S-sulindac inhibited carcinogen-induced CYP enzyme activity through direct inhibition as well as through decreased transcriptional activation of the AhR. S-sulindac induced expression of several carcinogen detoxification enzymes of the glutathione cycle including glutathione S-transferase A2, glutamate cysteine ligase catalytic subunit, glutamate cysteine ligase modifier subunit, and glutathione reductase. Conclusions: These results indicate that S-diclofenac and S-sulindac may serve as effective chemoprevention agents by favorably balancing the equation of carcinogen activation and detoxification mechanisms.
Nanoparticles: Health Effects—Pros and Cons
Authors: Maureen R. Gwinn, Val Vallyathan
Journal: Environmental Health Perspectives (2006)

With the advent of nanotechnology, the prospects for using engineered nanomaterials with diameters of < 100 nm in industrial applications, medical imaging, disease diagnoses, drug delivery, cancer treatment, gene therapy, and other areas have progressed rapidly. The potential for nanoparticles (NPs) in these areas is infinite, with novel new applications constantly being explored. The possible toxic health effects of these NPs associated with human exposure are unknown. Many fine particles generally considered "nuisance dusts" are likely to acquire unique surface properties when engineered to nanosize and may exhibit toxic biological effects. Consequently, the nuisance dust may be transported to distant sites and could induce adverse health effects. In addition the beneficial uses of NPs in drug delivery, cancer treatment, and gene therapy may cause unintentional human exposure. Because of our lack of knowledge about the health effects associated with NP exposure, we have an ethical duty to take precautionary measures regarding their use. In this review we highlight the possible toxic human health effects that can result from exposure to ultrafine particles (UFPs) generated by anthropogenic activities and their cardiopulmonary outcomes. The comparability of engineered NPs to UFPs suggests that the human health effects are likely to be similar. Therefore, it is prudent to elucidate their toxicologic effect to minimize occupational and environmental exposure. Highlighting the human health outcomes caused by UFPs is not intended to give a lesser importance to either the unprecedented technologic and industrial rewards of the nanotechnology or their beneficial human uses.
Characterization of the extravascular component of coronary resistance by instantaneous pressure-flow relationships in the dog.
Authors: R B Panerai, J H Chamberlain, B M Sayers
Journal: Circulation Research (1979)

To investigate the mechanical effects of the myocardium on the blood perfusion of the canine left ventricle, phasic total left ventricular (LV) coronary blood flow, perfusion pressure, LV pressure, aortic flow rate, and LV segment length were recorded continuously in an open-chested dog heart preparation.These variables were analyzed on a digital computer and time synchronized so that coronary pressure-flow curves could be drawn for various instants in the cardiac cycle.During diastole, the pressure-flow relationship is linear, changing to a nonlinear curve with the onset of systole.To estimate phasic patterns of coronary resistance and intramyocardial pressure (IMP), a model based on the vascular waterfall mechanism was developed and fitted to the experimental data.The results of this operation show inferred coronary resistance patterns that increase during ejection and remain constant during diastole and isovolumic contraction.Assuming LV pressure to represent endocardial IMP, the estimated epicardial IMP signal averages 42.1 ± 13.3% of peak LV pressure at this instant of peak pressure.Furthermore, increases in end-diastolic volume reduced the changes in inferred coronary resistance taking place during ejection, but the epicardial IMP signal remained practically unchanged.Circ Res 45: 378-390, 1979THE extravascular component of coronary resistance represents all the mechanical and hemodynamic effects imposed on the coronary circulation by the surrounding myocardial tissue (Snyder et al., 1975).Together with aortic pressure and autoregulation, the extravascular component is an important determinant of coronary blood flow, influencing not only its total value (Sabiston and Gregg, 1957), but also its regional distribution across the left ventricular wall (Moir, 1972).Intramyocardial compression in systole is thought to be greatest in the subendocardium and to decrease in more superficial muscle.Accordingly, during systole, flow is greatest in the subepicardial region and decreases toward the en-
THE INDOPHENOLOXYDASE CONTENT OF TISSUES FROM RABBITS INFECTED WITH PNEUMOCOCCUS
Authors: Florentin Medigreceanu
Journal: The Journal of Experimental Medicine (1914)

1. The action of indophenoloxydase is generally diminished in the tissues (liver, renal cortex, heart muscle) of rabbits that die of pneumococcus septicemia. The diminution is more frequent and marked in the liver and kidney than in the heart muscle. 2. The diminished activity of indophenoloxydase becomes more evident when the tissues undergo autolysis. At 37 degrees C. this ferment is much more easily destroyed in the tissues of the infected animals than in those from normal control animals (tables I, II, III, and IV). Exceptions are rare and they occur chiefly with the heart muscle. 3. Normal rabbit tissues, inoculated in vitro with pneumococcus culture, do not lose their indophenoloxydase much more quickly than do the normal controls, when they are kept either at room temperature or at 37 degrees C. (tables IV, V, VI, and VII). 4. It is therefore probable that the diminished activity of the indophenoloxydase of tissues from rabbits with pneumococcus septicemia is not due to the presence of the pneumococcus in these tissues, but that it is associated with a pathological change in the animal cell during life.
Glucocorticoids Downregulate Cyclooxygenase-1 Gene Expression and Prostacyclin Synthesis in Fetal Pulmonary Artery Endothelium
Authors: Sandy S. Jun, Zhong Chen, Margaret C. Pace, Philip W. Shaul
Journal: Circulation Research (1999)

Prostacyclin (prostaglandin I2 [PGI2]) is a key mediator of pulmonary vascular function during early postnatal life, and its production in the pulmonary vasculature rises markedly during that period because of increasing expression of cyclooxygenase type 1 (COX-1). The postnatal rise in COX-1 may be due to the release of inhibition by glucocorticoids, since plasma glucocorticoid levels fall after birth and glucocorticoids decrease PGI2 synthesis in certain nonpulmonary cell types. We therefore studied the direct effects of dexamethasone (DEX) on COX-1 expression in early-passage ovine fetal pulmonary-artery endothelial cells (PAECs). DEX (10(-10) to 10(-6) mol/L) caused a dose-related decrease in COX-1 mRNA expression that was evident by 24 hours, was maximal at 10(-6) mol/L (50% inhibition), and was not due to changes in mRNA stability. There was a parallel decline in COX-1 protein expression. COX-1 protein rose following DEX withdrawal, and DEX blunted the stimulatory effect of 17beta-estradiol on COX-1 expression. DEX alone (10(-8) mol/L for 48 hours) caused a 93% fall in basal PGI2 production, and bradykinin- and A23187-stimulated PGI2 were diminished 96% and 94%, respectively. Similarly, PGI2 synthesis from arachidonic acid fell 86% with DEX; all of the above effects are consistent with COX-1 downregulation. The glucocorticoid receptor (GR) antagonist mifepristone (RU-486; 10(-6) mol/L) blocked the inhibitory effect of DEX, and GR expression was evident by immunoblot analysis. These findings indicate that glucocorticoids downregulate COX-1 expression and PGI2 synthesis in fetal PAECs through the activation of PAEC GR and effects on COX-1 gene transcription. This mechanism may modulate pulmonary PGI2 production in the perinatal period, and it may also play a role in the effects of glucocorticoids on the systemic circulation at a variety of ages.
Genetic Diversity Patterns in the SR-BI/II Locus Can Be Explained by a Recent Selective Sweep
Authors: M. Le Jossec
Journal: Molecular Biology and Evolution (2004)

The human scavenger receptor class B type I (SR-BI and splice variant SR-BII) plays a central role in HDL cholesterol metabolism and represents a candidate gene for a number of related diseases. We examined the genetic diversity of its coding and flanking regions in a sample of 178 chromosomes from individuals of European, African, East Asian (including Southeast Asian), Middle-Eastern as well as Amerindian descent. Nine of the 14 polymorphisms observed are new. Four of the five variants causing amino acid replacements, G2S, S229G, R484W, and G499R, are likely to affect protein structure and function. SR-BI/BII diversity is partitioned among 19 haplotypes; all but one interconnected by single mutation or a recombination event. Such tight haplotype network and the unusual geographic partitioning of this diversity, high not only in Africa but in East Asia as well, suggests its recent origin and possible effect of selection. Coalescent analysis infers a relatively short time to the most recent common ancestor and points to population expansion in Africa and East Asia. These two continents differ significantly in pairwise FST values, differing as well from a single cluster formed by Europe, Middle East and America. In the context of findings for similarly analyzed other loci, we propose that a selective sweep at the origin of modern human populations could explain the low level of ancestral SR-BI/II diversity. The unusually deep split between Africa and Asia, well beyond the Upper Paleolithic when inferred under neutrality, is consistent with subsequent geographical and demographic expansion favoring the accumulation of new variants, especially in groups characterized by large effective population sizes, such as Asians and Africans. The relevance of such partitioning of SR-BI/II diversity remains to be investigated in genetic epidemiological studies which can be guided by the present findings.
Mineral Metabolism, Mortality, and Morbidity in Maintenance Hemodialysis
Authors: Geoffrey A. Block, Preston S. Klassen, J. Michael Lazarus, Norma Ofsthun, Edmund G. Lowrie, Glenn M. Chertow
Journal: Journal of the American Society of Nephrology (2004)

Mortality rates in ESRD are unacceptably high. Disorders of mineral metabolism (hyperphosphatemia, hypercalcemia, and secondary hyperparathyroidism) are potentially modifiable. For determining associations among disorders of mineral metabolism, mortality, and morbidity in hemodialysis patients, data on 40,538 hemodialysis patients with at least one determination of serum phosphorus and calcium during the last 3 mo of 1997 were analyzed. Unadjusted, case mix-adjusted, and multivariable-adjusted relative risks of death were calculated for categories of serum phosphorus, calcium, calcium x phosphorus product, and intact parathyroid hormone (PTH) using proportional hazards regression. Also determined was whether disorders of mineral metabolism were associated with all-cause, cardiovascular, infection-related, fracture-related, and vascular access-related hospitalization. After adjustment for case mix and laboratory variables, serum phosphorus concentrations >5.0 mg/dl were associated with an increased relative risk of death (1.07, 1.25, 1.43, 1.67, and 2.02 for serum phosphorus 5.0 to 6.0, 6.0 to 7.0, 7.0 to 8.0, 8.0 to 9.0, and >/=9.0 mg/dl). Higher adjusted serum calcium concentrations were also associated with an increased risk of death, even when examined within narrow ranges of serum phosphorus. Moderate to severe hyperparathyroidism (PTH concentrations >/=600 pg/ml) was associated with an increase in the relative risk of death, whereas more modest increases in PTH were not. When examined collectively, the population attributable risk percentage for disorders of mineral metabolism was 17.5%, owing largely to the high prevalence of hyperphosphatemia. Hyperphosphatemia and hyperparathyroidism were significantly associated with all-cause, cardiovascular, and fracture-related hospitalization. Disorders of mineral metabolism are independently associated with mortality and morbidity associated with cardiovascular disease and fracture in hemodialysis patients.
Efficacy of troglitazone on body fat distribution in type 2 diabetes.
Authors: S Akazawa, F Sun, M Ito, E Kawasaki, K Eguchi
Journal: Diabetes Care (2000)

OBJECTIVE: The insulin-sensitizing action of troglitazone may be mediated through the activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and the promotion of preadipocyte differentiation in adipose tissue on which troglitazone has depot-specific effects. We investigated the relationship between efficacy of the drug and body fat distribution. Changes in body fat distribution were also investigated by long-term administration of the drug. RESEARCH DESIGN AND METHODS: Troglitazone was given at a dose of 400 mg/day to 20 patients with type 2 diabetes whose diet and sulfonylurea therapy produced unsatisfactory glycemic control (HbA(1c) &amp;gt;7.8%) and whose insulin secretory capacity was found to be preserved (postprandial C-peptide &amp;gt;3 ng/ml). HbA(1c) values, serum lipid levels, and body weight were measured monthly Body fat distribution was evaluated in subcutaneous (SC) and visceral fat using a computed tomography scan at umbilical levels before and after troglitazone therapy RESULTS: During the 1-year troglitazone treatment, HbA(1c) was significantly decreased (from 9.2 +/- 0.2 to 7.1 +/- 0.2%, P &amp;lt; 0.01), showing lowest values at 4-6 months, whereas body weight was significantly increased (BMI 24.6 +/- 0.6 to 25.7 +/- 0.6 kg/m2, P &amp;lt; 0.01). Reduction of HbA(1c) (deltaHbA(1c)) from the baseline value during treatment was significantly greater in obese patients (BMI &amp;gt;26 kg/m2) than in nonobese patients (-3.2 +/- 0.4 vs. -2.1 +/- 0.3%, P &amp;lt; 0.05) and was more significant in women than in men (-3.2 +/- 0.2 vs. - 1.4 +/- 0.2%, P &amp;lt; 0.01). The level of deltaHbA(1c) during treatment showed a significant negative correlation with SC fat area (r = -0.742, P &amp;lt; 0.01) but not with visceral fat area. Weight gain during troglitazone treatment resulted in increased accumulation of SC fat without a change in visceral fat area and, consequently. in a significant decrease in the visceral-to-SC fat ratio. CONCLUSIONS: Predominant accumulation of SC fat for the visceral fat tissue was an important predictor of the efficacy of troglitazone therapy in patients with type 2 diabetes. Greater efficacy of troglitazone was observed in women who were characterized by more accumulation of SC adipose tissue than men. Long-term administration of the drug resulted in weight gain with increased accumulation of SC adipose tissue, probably because of the activation of PPAR-gamma in the region.
Individual allergens as risk factors for bronchial responsiveness in young adults
Authors: S. Chinn, D. Jarvis, C. Luczynska, P. Burney
Journal: Thorax (1998)

<h3>BACKGROUND</h3> Bronchial responsiveness is known to be related to atopy, but the relative contribution of sensitisation to individual allergens in the UK, or whether serum total IgE is an independent risk factor, is unknown. <h3>METHODS</h3> A random sample of 1864 men and women aged 20–44 years, drawn from family health service registers in Cambridge, Ipswich and Norwich, was invited to answer a detailed questionnaire, undergo skin prick tests and methacholine bronchial challenge, and provide a serum sample for measurement of total and specific IgE. The relation of bronchial responsiveness to risk factors was studied in 749 subjects (40.2%) with complete data. <h3>RESULTS</h3> Bronchial responsiveness was increased in those sensitised to cat,<i>D pteronyssinus</i>, Timothy grass and<i>Cladosporium</i>, but decreased in subjects also positive to birch allergen. Additional skin prick tests added little information. Serum total IgE was not significantly related after adjustment for specific IgE to the five allergens. Increasing titres of specific IgE to <i>D pteronyssinus</i> were associated with increasing bronchial responsiveness. Specific IgE to<i>Cladosporium</i> had a prevalence of around 3%, but was associated with greatly increased responsiveness. Decreased baseline lung function was related (p&lt;0.001) to increased responsiveness. There was an interaction between age and smoking status, with lower responsiveness in older non-smokers. <h3>CONCLUSION</h3> Atopy is the most important risk factor for bronchial responsiveness in this age group, but effects are not additive across all allergens. Research in reducing exposure to house dust mite should also address the role of<i>Cladosporium</i> sensitisation and exposure to indoor moulds.
Thymic Selection Generates a Large T Cell Pool Recognizing a Self-Peptide in Humans
Authors: Alfred Zippelius, Mikaël J. Pittet, Pascal Batard, Nathalie Rufer, Magda de Smedt, Philippe Guillaume, Kim Ellefsen, Danila Valmori, Danielle Liénard, Jean Plum, H. Robson MacDonald, Daniel E. Speiser, Jean-Charles Cerottini, Pedro Romero
Journal: The Journal of Experimental Medicine (2002)

The low frequency of self-peptide–specific T cells in the human preimmune repertoire has so far precluded their direct evaluation. Here, we report an unexpected high frequency of T cells specific for the self-antigen Melan-A/MART-1 in CD8 single–positive thymocytes from human histocompatibility leukocyte antigen-A2 healthy individuals, which is maintained in the peripheral blood of newborns and adults. Postthymic replicative history of Melan-A/MART-1–specific CD8 T cells was independently assessed by quantifying T cell receptor excision circles and telomere length ex vivo. We provide direct evidence that the large T cell pool specific for the self-antigen Melan-A/MART-1 is mostly generated by thymic output of a high number of precursors. This represents the only known naive self-peptide–specific T cell repertoire directly accessible in humans.