Experience of fatigue, and its relationship to physical capacity and disease severity in men and women with COPD

Kristina Tödt,1,2 Elisabeth Skargren,3 Magnus Kentson,4 Kersti Theander,5,6 Per Jakobsson,2 Mitra Unosson1 1Department of Social and Welfare Studies, Faculty of Health Sciences, Linköping University, Norrköping, Sweden; 2Department of Pulmonary Medicine, University Hospital, 3Department of Medicine and Health, Faculty of Health Sciences, Linköping University, Linköping, Sweden; 4Department of Pulmonary Medicine, Ryhov Hospital, Jönköping, Sweden; 5Department of Nursing, Faculty of Social and Life Sciences, Karlstad University, Karlstad, Sweden; 6Primary Care Research Unit, County Council of Värmland, Sweden Introduction: Several differences have been reported in the clinical characteristics of chronic obstructive pulmonary disease (COPD) between men and women. Differences have been found in the association between respiratory symptoms and lung function, and in the factors associated with dyspnea. This raises the question of whether there are differences between the sexes in the relationship between fatigue, the second most prevalent symptom, and the variables of physical capacity and disease severity. Objectives: To examine the experience of fatigue and its relationship to physical capacity and disease severity in men and women with COPD. Methods: In a cross-sectional study 121 patients with COPD (54 men and 67 women), the experience of fatigue (frequency, duration, and severity) and physical capacity (lung function, 6-minute walk distance [6MWD], grip strength, and timed-stand test) were assessed. Disease severity was graded according to the Body mass index, airway Obstruction, Dyspnoea and Exercise capacity (BODE) index. Two multiple logistic regression models were tested, both of which were performed separately in men and women, to examine the association between the experience of fatigue and variables of physical capacity and the BODE index. Results: Eighty-nine (73.6%) patients experienced fatigue, with similar proportions in men and women. The men with fatigue had worse physical capacity and more severe disease than did the men without fatigue: for men with and without fatigue, respectively, the percent of predicted forced expiratory volume in 1 second (FEV1) (mean [standard deviation]) was 47 (14) vs 64 (17); the 6MWD (mean [standard deviation]) was 398 (138) vs 539 (105) m; and the BODE index (median [quartile 1-3]) was 3 (2–5) vs 1 (0–1) (P<0.01). In women, only higher leg fatigue post-6MWD was seen among those experiencing fatigue compared with women without fatigue: for women with and without fatigue, respectively, leg fatigue (median [quartile 1-3]) was 4 (3–5) vs 2 (0–3) (P<0.001). The regression models showed that the 6MWD and the BODE index were associated with fatigue in both men and women, but in women, leg fatigue remained an independent associate in both models. Conclusion: Exercise capacity and disease severity were associated with fatigue in both men and women. In women, leg fatigue was strongly associated with fatigue, which warrants further investigation. Keywords: chronic obstructive pulmonary disease, disease state, functional capacity, sex differences, symptom experience, leg fatigu

Oxidant-induced autophagy and ferritin degradation contribute to epithelial–mesenchymal transition through lysosomal iron

Apostolos Sioutas,1 Linda K Vainikka,2 Magnus Kentson,3 Sören Dam-Larsen,4 Urban Wennerström,5 Petra Jacobson,1 Hans Lennart Persson1 1Division of Respiratory Medicine, Department of Medical and Health Sciences, 2Division of Experimental Pathology, Department of Clinical and Experimental Medicine, Linköping University, Linköping,3Division of Medicine, Ryhov Hospital, Jönköping, 4Division of Medicine, Hospital of Eksjö, Eksjö, 5Division of Medicine, Hospital of Västervik, Västervik, Sweden Purpose: Transforming growth factor (TGF)-β1 triggers epithelial–mesenchymal transition (EMT) through autophagy, which is partly driven by reactive oxygen species (ROS). The aim of this study was to determine whether leaking lysosomes and enhanced degradation of H-ferritin could be involved in EMT and whether it could be possible to prevent EMT by iron chelation targeting of the lysosome. Materials and methods: EMT, H-ferritin, and autophagy were evaluated in TGF-β1-stimulated A549 human lung epithelial cells cultured in vitro using Western blotting, with the additional morphological assessment of EMT. By using immunofluorescence and flow cytometry, lysosomes and ROS were assessed by acridine orange and 6-carboxy-2’,7’-dichlorodihydrofluorescein acetate assays, respectively. Results: TGF-β1-stimulated cells demonstrated a loss of H-ferritin, which was prevented by the antioxidant N-acetyl-L-cysteine (NAC) and inhibitors of lysosomal degradation. TGF-β1 stimulation generated ROS and autophagosome formation and led to EMT, which was further promoted by the additional ROS-generating cytokine, tumor necrosis factor-α. Lysosomes of TGF-β1-stimulated cells were sensitized to oxidants but also completely protected by lysosomal loading with dextran-bound deferoxamine (DFO). Autophagy and EMT were prevented by NAC, DFO, and inhibitors of autophagy and lysosomal degradation. Conclusion: The findings of this study support the role of enhanced autophagic degradation of H-ferritin as a mechanism for increasing the vulnerability of lysosomes to iron-driven oxidant injury that triggers further autophagy during EMT. This study proposes that lysosomal leakage is a novel pathway of TGF-β1-induced EMT that may be prevented by iron-chelating drugs that target the lysosome. Keywords: A549 cells, pulmonary disease, transforming growth factor, pulmonary fibrosis, tumor necrosis factor, COP

Current decision rules in fetal surveillance are suboptimal

Abstract S-115 for Poster Session: Perinatology: Risk Factors, Outcomes, MortalityJJ Kaandorp, AJ Mesker, S Loix, F de Boer, E Kentson, M Kleppe, JH Baalman, E Schuit, MJ Benders, GH Visser, JB Derks, BW Mo

Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK inhibition as an Effective Strategy.

PURPOSE: Venetoclax-based therapy is a standard of care option in front-line and relapsed/refractory CLL. Patient management following venetoclax discontinuation remains non-standard and poorly understood. EXPERIMENTAL DESIGN: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Co-primary endpoints were overall response rate (ORR) and progression free survival (PFS) for the post-venetoclax treatments stratified by treatment type (BTKi, PI3Ki, and cellular therapies). RESULTS: We identified CLL patients who discontinued venetoclax in the front-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (n=130), and 81% were idelalisib naïve (n=263). ORR to BTKi was 84% (n=44) in BTKi-naïve patients vs. 54% (n=30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons. CONCLUSIONS: For BTKi naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies