Proteins Inform Survival-Based Differences in Patients with Glioblastoma

Background: Improving the care of patients with glioblastoma (GB) requires accurate and reliable predictors of patient prognosis. Unfortunately, while protein markers are an effective readout of cellular function, proteomics has been underutilized in GB prognostic marker discovery. Methods: For this study, GB patients were prospectively recruited and proteomics discovery using liquid chromatography-mass spectrometry analysis (LC-MS/MS) was performed for 27 patients including 13 short-term survivors (STS) (≤10 months) and 14 long-term survivors (LTS) (≥18 months). Results: Proteomics discovery identified 11 941 peptides in 2495 unique proteins, with 469 proteins exhibiting significant dysregulation when comparing STS to LTS. We verified the differential abundance of 67 out of these 469 proteins in a small previously published independent dataset. Proteins involved in axon guidance were upregulated in STS compared to LTS, while those involved in p53 signaling were upregulated in LTS. We also assessed the correlation between LS MS/MS data with RNAseq data from the same discovery patients and found a low correlation between protein abundance and mRNA expression. Finally, using LC-MS/MS on a set of 18 samples from 6 patients, we quantified the intratumoral heterogeneity of more than 2256 proteins in the multisample dataset. Conclusions: These proteomic datasets and noted protein variations present a beneficial resource for better predicting patient outcome and investigating potential therapeutic targets

A Proteomic Analysis of Human Cilia: Identification of Novel Components

Cilia play an essential role in protecting the respiratory tract by providing the force necessary for mucociliary clearance. Although the major structural components of human cilia have been described, a complete understanding of cilia function and regulation will require identification and characterization of all ciliary components. Estimates from studies o

Effect of CPAP-withdrawal on blood pressure in OSA: data from three randomized-controlled trials

Background Based on meta-analyses, the blood pressure (BP) lowering effect of continuous positive airway pressure (CPAP) therapy in patients with obstructive sleep apnea (OSA) is reported to be approximately 2-3mmHg. This figure is derived from heterogeneous trials, often limited by poor CPAP-adherence, and thus possibly underestimating the treatment effect. We analyzed morning BP data from three randomized controlled CPAP withdrawal trials which included only patients with optimal CPAP-compliance. Methods Within the three trials, 149 OSA patients on CPAP were randomized to continue therapeutic CPAP (n=65) or to withdraw CPAP (n=84) for two weeks. Morning BP was measured at home before, and after sleep studies in hospital. Results CPAP-withdrawal was associated with a return of OSA (apnea-hypopnea index (AHI) at baseline 2.8/h, at follow-up 33.2/h). Systolic office BP increased in the CPAP-withdrawal group, compared to CPAP-continuation, by +5.4mmHg (95%CI 1.8-8.9mmHg, p=0.003), and systolic home BP by +9.0mmHg (95%-CI 5.7-12.3mmHg, p&lt;0.001). Diastolic office BP increased by +5.0mmHg (95%CI 2.7-7.3mmHg, p&lt;0.001), and diastolic home BP by +7.8mmHg (95%CI 5.6-10.4mmHg, p&lt;0.001). AHI, baseline home systolic BP, statin usage, gender, and number of antihypertensive drugs were all independently associated with systolic BP change in multivariate analysis, controlling for age, BMI, smoking, diabetes, and sleepiness. Conclusions CPAP-withdrawal results in a clinically relevant increase in BP, which is considerably higher than in conventional CPAP trials, and is also underestimated when office BP is used. Greater OSA severity is associated with a higher BP rise in response to CPAP-withdrawal. </p

Effect of CPAP-withdrawal on blood pressure in OSA: data from three randomized-controlled trials

Background Based on meta-analyses, the blood pressure (BP) lowering effect of continuous positive airway pressure (CPAP) therapy in patients with obstructive sleep apnea (OSA) is reported to be approximately 2-3mmHg. This figure is derived from heterogeneous trials, often limited by poor CPAP-adherence, and thus possibly underestimating the treatment effect. We analyzed morning BP data from three randomized controlled CPAP withdrawal trials which included only patients with optimal CPAP-compliance. Methods Within the three trials, 149 OSA patients on CPAP were randomized to continue therapeutic CPAP (n=65) or to withdraw CPAP (n=84) for two weeks. Morning BP was measured at home before, and after sleep studies in hospital. Results CPAP-withdrawal was associated with a return of OSA (apnea-hypopnea index (AHI) at baseline 2.8/h, at follow-up 33.2/h). Systolic office BP increased in the CPAP-withdrawal group, compared to CPAP-continuation, by +5.4mmHg (95%CI 1.8-8.9mmHg, p=0.003), and systolic home BP by +9.0mmHg (95%-CI 5.7-12.3mmHg, p AHI, baseline home systolic BP, statin usage, gender, and number of antihypertensive drugs were all independently associated with systolic BP change in multivariate analysis, controlling for age, BMI, smoking, diabetes, and sleepiness. </p Conclusions CPAP-withdrawal results in a clinically relevant increase in BP, which is considerably higher than in conventional CPAP trials, and is also underestimated when office BP is used. Greater OSA severity is associated with a higher BP rise in response to CPAP-withdrawal. </p

ECG risk markers for atrial fibrillation and sudden cardiac death in minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised trial.

Obstructive sleep apnoea (OSA), atrial fibrillation (AF) and sudden cardiac death (SCD) may occur concomitantly, and are of considerable epidemiological interest, potentially leading to morbidity and mortality. Effective treatment of OSA with continuous positive airway pressure (CPAP) could prevent progression and/or recurrence of AF and factors leading to SCD. Recently, a randomised controlled trial showed a statistically and clinically significant prolongation of measures of cardiac repolarisation after CPAP withdrawal in symptomatic patients with moderate to severe OSA. Whether or not CPAP therapy improves ECG risk markers of AF and SCD in patients with minimally symptomatic OSA as well, is unknown.3 centres taking part in the MOSAIC (Multicentre Obstructive Sleep Apnoea Interventional Cardiovascular) trial randomisd 303 patients with minimally symptomatic OSA to receive either CPAP or standard care for 6 months. Treatment effects of CPAP on P-wave duration, P-wave dispersion, QT interval, QT dispersion, Tpeak-to-Tend (TpTe) and TpTe/QT ratio were analysed.Participants were primarily men (83%). Mean age was 57.8 (7.2) and mean ODI (Oxygen Desaturation Index) at baseline was 13.1/h (12.3). Full 12-lead ECG data was available in 250 patients. Mean (SD) baseline intervals of P-wave duration, P-wave dispersion, QTc interval, QT dispersion, TpTe and TpTe/QT ratio in ms were 87.4 (8.3), 42.3 (11.9), 397.8 (22.7), 43.1 (16.7), 73.5 (13.7) and 0.19 (0.0), respectively. No treatment effect of CPAP on risk markers for AF and SCD was found.There seems to be no effect of CPAP on ECG measures of arrhythmia risk in patients with minimally symptomatic OSA.ISRCTN34164388; Post-results

Nocturnal cerebral hypoxia in obstructive sleep apnoea: a randomised controlled trial

Cerebral hypoxia may promote cerebral damage in patients with obstructive sleep apnoea (OSA). We investigated whether OSA patients experience nocturnal cerebral hypoxia that is prevented by continuous positive airway pressure (CPAP). OSA patients using CPAP underwent sleep studies including pulse oximetry (arterial oxygen saturation (SpO2)) and near-infrared spectroscopy to monitor cerebral tissue oxygenation (CTO) at baseline and after 2 weeks on either subtherapeutic or therapeutic CPAP according to randomised allocation. Changes in oxygenation at end of the 2-week intervention were compared between groups. Among 21 patients (mean apnoea/hypopnoea index 50.3 events·h−1), OSA recurred in all nine patients using subtherapeutic CPAP and in none of the patients using therapeutic CPAP: mean (95% CI) between-group differences in changes of oxygen desaturation index from baseline to 2 weeks +40.7 (31.1–50.4) events·h−1 for SpO2 and +37.0 (25.3–48.7) events·h−1 for CTO (both p&lt;0.001). Mean nocturnal SpO2 and CTO decreased more in patients using subtherapeutic versus therapeutic CPAP: −2.4 (−3.4–−1.1)% and −3.8 (−7.4–−0.1)%, respectively; both p&lt;0.03. Severe CTO drops ≥13% associated with cerebral dysfunction in previous studies occurred in four out of nine patients using subtherapeutic CPAP, but in none out of 12 patients using therapeutic CPAP (p=0.01). In patients with OSA, CPAP withdrawal resulted in nocturnal cerebral deoxygenation, suggesting a role of cerebral hypoxia in predisposing untreated OSA patients to cerebral damage.</p

Effect of CPAP withdrawal on myocardial perfusion in OSA - a randomized controlled trial

Background and objective Obstructive sleep apnoea (OSA) is highly prevalent and associated with an increased incidence of cardiovascular events. Endothelial dysfunction is the proposed causative mechanism. Continuous positive airway pressure (CPAP) is presumed to improve cardiovascular outcome in OSA. CPAP withdrawal was recently shown to lead to peripheral endothelial dysfunction. However, it is not known whether short-term CPAP withdrawal reduces myocardial perfusion in OSA. Methods In this double-blind randomized controlled study, 45 patients with moderate to severe OSA previously adherent to CPAP were assigned to either subtherapeutic or continuing therapeutic CPAP for 2 weeks. The primary outcome was adenosine-induced myocardial blood flow (MBF) as a measure of endothelial function, assessed by 13N-ammonia positron emission tomography. Secondary outcomes were measures of dermal and renal microvascular function, morning blood pressure (BP) and heart rate. Results Despite return of OSA associated with significant increases in BP (+9.1 mm Hg, 95% CI +4.9 to +13.4 mm Hg, P &lt; 0.001) and heart rate (+9.6 bpm, 95% confidence interval (CI) +4.6 to +14.6 bpm, P &lt; 0.001), CPAP withdrawal had no significant effect on maximal myocardial perfusion capacity (hyperaemic MBF −0.01 ml/min/g, 95% CI −0.33 to +0.24 ml/min/g, P = 0.91), nor renal and dermal microvascular function. Conclusion In patients with OSA, a short-term CPAP withdrawal does not lead to detectable impairment of coronary endothelial function, as has been demonstrated in the brachial artery, despite a clinically relevant increase in BP of nearly 10 mm Hg. There was also no evidence of an impairment of renal or dermal microvascular function

Effect of continuous positive airway pressure therapy on circadian patterns of cardiac repolarization in patients with obstructive sleep apnoea: data from a randomized trial

BACKGROUND: Regular airway clearance by chest physiotherapy and/or exercise is critical to lung health in cystic fibrosis (CF). Combination of cycling exercise and chest physiotherapy using the Flutter® device on sputum properties has not yet been investigated. METHODS: This prospective, randomized crossover study compared a single bout of continuous cycling exercise at moderate intensity (experiment A, control condition) vs a combination of interval cycling exercise plus Flutter® (experiment B). Sputum properties (viscoelasticity, yield stress, solids content, spinnability, and ease of sputum expectoration), pulmonary diffusing capacity for nitric oxide (DLNO) and carbon monoxide (DLCO) were assessed at rest, directly and 45 min post-exercise (recovery) at 2 consecutive visits. Primary outcome was change in sputum viscoelasticity (G', storage modulus; G", loss modulus) over a broad frequency range (0.1-100 rad.s- 1). RESULTS: 15 adults with CF (FEV1range 24-94% predicted) completed all experiments. No consistent differences between experiments were observed for G' and G" and other sputum properties, except for ease of sputum expectoration during recovery favoring experiment A. DLNO, DLCO, alveolar volume (VA) and pulmonary capillary blood volume (Vcap) increased during experiment A, while DLCO and Vcap increased during experiment B (all P 430 ms). In these patients, CPAP led to reductions in QTc, allowing reclassification into lower risk-associated values of QTc (<430 ms). Conclusions In this exploratory study, CPAP treatment led to an overall reduction in the QTc-interval compared with subtherapeutic CPAP. This reduction seems more pronounced during evening hours and in patients with a QTc above 430 ms.experiment A (P = 0.032). CONCLUSIONS: The additional use of the Flutter® to moderate intensity interval cycling exercise has no measurable effect on the viscoelastic properties of sputum compared to moderate intensity continuous cycling alone. Elevations in diffusing capacity represent an acute exercise-induced effect not sustained post-exercise