The objective of the present study was to evaluate a comprehensive set of urinary biomarkers for oxidative damage to lipids, proteins and DNA, in man. Eighteen moderately trained males (mean age 24.6+/-0.7) exercised 60min at 70% of maximal O2 uptake on a cycle ergometer. Urine fractions for 12 h were collected 1 day before, and for 3 consecutive days after exercise. As biomarkers of lipid peroxidation, 8 aldehydes (i.e. propanal, butanal, pentanal, hexanal, heptanal, octanal, nonanal and malondialdehyde-MDA)and acetone were analyzed in urines by gas chromatography with electron capture detection (GC-ECD). As a biomarker of protein oxidation, o,o'-dityrosine was analyzed in urine samples by a recently developed isotope dilution HPLC-atmospheric pressure chemical ionization (APCI)-tandem-mass spectrometry (HPLC-APCI-MS/MS) methodology. As a biomarker of oxidative DNA damage, urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG) was measured by an ELISA method. On the day of exercise, significant increases were observed in urinary excretions of acetone (p < 0.025, n = 18) and butanal (p < 0.01, n = 18) in the 12h daytime fractions compared to the daytime fraction before exercise. The urinary acetone excretion was also significantly (p < 0.05) increased on the 1st day after exercise. Octanal and nonanal were increased in the daytime urine fraction on the 2nd day after exercise. However, these increases were of borderline significance (p = 0.09 and p = 0.07, respectively). Significantly elevated urinary o,o'-dityrosine amounts were observed in the daytime fraction on the day of exercise (p < 0.025) and on the 1st day after exercise (p = 0.07) compared to the before exercise daytime fraction. Excretion of urinary 8-OHdG was statistically significantly increased in the daytime fractions on the day of exercise (p = 0.07) and on the 1st day after exercise (p < 0.025) compared to before exercise daytime fraction. Increases in urinary excretions of acetone, propanal, pentanal, MDA and 8-OHdG significantly correlated with training status (hours of exercise/week) of the volunteers, while o,o'-dityrosine did not. To our knowledge, the present study is the first to evaluate a multi-parameter non-invasive biomarker set for damage to three main cellular targets of ROS. It shows that 1 h of exercise may already induce oxidative damage in moderately trained individuals and that the chosen urinary biomarkers are sensitive enough to monitor such damage.
The ability of purified human neutrophil elastase (EC 3.4.21.37) to cleave native type I collagen has been investigated. Soluble human, bovine or rat type I collagen was incubated with neutrophil elastase for 16 h at 25 degrees C before catalysis was stopped with 3, 4-dichloroisocoumarin. Analysis by SDS/PAGE of the collagen digests revealed 3/4-length fragments similar in size to those produced by interstitial collagenase. The collagenolytic activity was dose dependent and was not due to a contaminating metalloproteinase or cysteine proteinase, as it was not inhibited by 1,10-phenanthroline, EDTA or L-trans-epoxysuccinyl-leucylamido-(4-guanidino)butane. The identity of the cleavage products was confirmed using a new antibody that recognizes the unwound alpha2(I)-chain. This detected the 3/4-length fragment of type I collagen following neutrophil elastase cleavage. In addition to cleaving soluble collagen, neutrophil elastase also cleaved reconstituted, radiolabelled type I collagen fibrils, at a rate of 16 microg/min per nmol. These results indicate that neutrophil elastase can cleave native type I collagen in the helix, an activity that might contribute to its roles in connective-tissue pathology.
This study evaluates the effects of training with noninvasive ventilatory support in patients with chronic obstructive pulmonary disease in a randomised, controlled, observerblinded trial.Twenty-nine patients with chronic obstructive pulmonary disease and with a ventilatory limited exercise capacity (forced expiratory volume in one second ,60% predicted, breathing reserve at maximal exercise ,20% of maximally voluntary ventilation, resting arterial oxygen tension o8 kPa (60 mmHg), end-exercise arterial oxygen saturation measured by pulse oximetry o85%) completed an 8-week supervised outpatient cycle exercise programme. Fourteen patients were randomised to training with inspiratory pressure support of 10 cmH 2 O and 15 patients to training with control (sham) inspiratory pressure support of 5 cmH 2 O. Outcome measures were the incremental shuttle walking test and a constant-load cycle endurance test at 75% of peak work rate including the measurement of physiological responses, and health status measured using the St. George's Respiratory Questionnaire.Statistically significant between-group differences were found in favour of the inspiratory pressure support of 10 cmH 2 O group for improvement in shuttle walking distance (16¡17 versus 3¡13%), cycle endurance (164¡124 versus 88¡128%), and the reduction in minute ventilation during exercise (-11¡10 versus -2¡9%).It was concluded that exercise training with inspiratory pressure support of 10 cmH 2 O resulted in statistically significantly larger improvements in exercise performance than training with inspiratory pressure support of 5 cmH 2 O in patients with chronic obstructive pulmonary disease suffering from a ventilatory limited exercise capacity. Inspiratory pressure support of 10 cmH 2 O may be considered as adjunct during high-intensity exercise training.
Key Points• High proportions of PD-1 1 and PD-L1 1 leukocytes in the Hodgkin lymphoma microenvironment are associated with inferior outcome.• Expression of PD-L1 and PD-L2 on Hodgkin and Reed-Sternberg cells has no impact on outcome.Immune checkpoint inhibition targeting the programmed death receptor (PD)-1 pathway is a novel treatment approach in relapsed and refractory classical Hodgkin lymphoma (cHL). leukocytes was also associated with inferior OS in a multivariate analysis (HR, 3.46; 95% CI,. This is the first study to show a correlation after multivariate analysis between inferior outcome in cHL and a high proportion of both PD-1 1 and PD-L1 1 leukocytes in the tumor microenvironment.
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