Disturbed balance of expression between XIAP and Smac/DIABLO during tumour progression in renal cell carcinomas

Dysregulation of apoptosis plays an important role in tumour progression and resistance to chemotherapy. The X-linked inhibitor of apoptosis ( XIAP) is considered to be the most potent caspase inhibitor of all known inhibitor of apoptosis-family members. Only recently, an antagonist of XIAP has been identified, termed Smac/DIABLO. To explore the relevance of antiapoptotic XIAP and proapoptotic Smac/DIABLO for tumour progression in renal cell carcinomas (RCCs), we analysed XIAP and Smac/DIABLO mRNA and protein expression in the primary tumour tissue from 66 RCCs of all major histological types by quantitative real-time PCR, Western blot and ELISA. X-linked inhibitor of apoptosis and Smac/DIABLO mRNA expression was found in all RCCs. Importantly, the relative XIAP mRNA expression levels significantly increased from early (pT1) to advanced (pT3) tumour stages ( P = 0.0002) and also with tumour dedifferentiation ( P = 0.04). Western blot analysis confirmed the tumour stage-dependent increase of XIAP expression on the protein level. In contrast, mRNA and protein expression levels of Smac/DIABLO did not significantly change between early and advanced tumour stages or between low and high tumour grades. Consequently, the mRNA expression ratio between antiapoptotic XIAP and proapoptotic Smac/DIABLO markedly increased during progression from early ( pT1) to advanced ( pT3) tumour stages. Moreover, RCCs confined within the organ capsule ( pT1 and pT2) exhibited a significantly lower XIAP to Smac/DIABLO expression ratio when compared with RCCs infiltrating beyond the kidney ( pT3; P = 0.01). Thus, our investigation demonstrates that the delicate balance between XIAP and Smac/DIABLO expression is gradually disturbed during progression of RCCs, resulting in a relative increase of antiapoptotic XIAP over proapoptotic Smac/DIABLO, thereby probably contributing to the marked apoptosis resistance of RCC.OncologySCI(E)46ARTICLE71349-13579

Physical activity assessment by accelerometry in people with heart failure

Background: International guidelines for physical activity recommend at least 150 min per week of moderate-to-vigorous physical activity (MVPA) for adults, including those with cardiac disease. There is yet to be consensus on the most appropriate way to categorise raw accelerometer data into behaviourally relevant metrics such as intensity, especially in chronic disease populations. Therefore the aim of this study was to estimate acceleration values corresponding to inactivity and MVPA during daily living activities of patients with heart failure (HF), via calibration with oxygen consumption (VO2) and to compare these values to previously published, commonly applied PA intensity thresholds which are based on healthy adults. Methods: Twenty-two adults with HF (mean age 71 ± 14 years) undertook a range of daily living activities (including laying down, sitting, standing and walking) whilst measuring PA via wrist- and hip-worn accelerometers and VO2 via indirect calorimetry. Raw accelerometer output was used to compute PA in units of milligravity (mg). Energy expenditure across each of the activities was converted into measured METs (VO2/resting metabolic rate) and standard METs (VO2/3.5 ml/kg/min). PA energy costs were also compared with predicted METs in the compendium of physical activities. Location specific activity intensity thresholds were established via multilevel mixed effects linear regression and receiver operator characteristic curve analysis. A leave-one-out method was used to cross-validate the thresholds. Results: Accelerometer values corresponding with intensity thresholds for inactivity ( 50% lower than previously published intensity thresholds for both wrists and waist accelerometers (inactivity: 16.7 to 18.6 mg versus 45.8 mg; MVPA: 43.1 to 49.0 mg versus 93.2 to 100 mg). Measured METs were higher than both standard METs (34-35%) and predicted METs (45-105%) across all standing and walking activities. Conclusion: HF specific accelerometer intensity thresholds for inactivity and MVPA are lower than previously published thresholds based on healthy adults, due to lower resting metabolic rate and greater energy expenditure during daily living activities for HF patients. Trial registration: Clinical trials.gov NCT03659877, retrospectively registered on September 6th 2018.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This study was undertaken as part of a PhD, which was funded by a University of Exeter Postgraduate Studentship Grant. The funders were not involved in design of the study, data collection, analysis, and interpretation of data, and in writing the manuscript.published version, accepted versio

Heterogeneous treatment effects of therapeutic-dose heparin in patients hospitalized for COVID-19

Importance Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures Organ support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI 90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Conclusions and Relevance Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. Trial Registration ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT0437258