SMER28 attenuates PI3K/mTOR signaling by direct inhibition of PI3K p110 delta

SMER28 (Small molecule enhancer of Rapamycin 28) is an autophagy-inducing compound functioning by a hitherto unknown mechanism. Here, we confirm its autophagy-inducing effect by assessing classical autophagy-related parameters. Interestingly, we also discovered several additional effects of SMER28, including growth retardation and reduced G1 to S phase progression. Most strikingly, SMER28 treatment led to a complete arrest of receptor tyrosine kinase signaling, and, consequently, growth factor-induced cell scattering and dorsal ruffle formation. This coincided with a dramatic reduction in phosphorylation patterns of PI3K downstream effectors. Consistently, SMER28 directly inhibited PI3Kδ and to a lesser extent p110γ. The biological relevance of our observations was underscored by SMER28 interfering with InlB-mediated host cell entry of Listeria monocytogenes, which requires signaling through the prominent receptor tyrosine kinase c-Met. This effect was signaling-specific, since entry of unrelated, gram-negative Salmonella Typhimurium was not inhibited. Lastly, in B cell lymphoma cells, which predominantly depend on tonic signaling through PI3Kδ, apoptosis upon SMER28 treatment is profound in comparison to non-hematopoietic cells. This indicates SMER28 as a possible drug candidate for the treatment of diseases that derive from aberrant PI3Kδ activity

Exercise in severe COPD: Is walking different from stair-climbing?

SummaryBackgroundIt remains unclear whether the 6-min walking test can predict performance during stair-climbing in severe COPD patients. The present study aimed to assess different pathophysiological changes between walking and stair-climbing in these patients.MethodsSixteen COPD patients (mean FEV1 33±13% predicted) underwent a 6-min walking test and performed stair-climbing (44 steps) in a randomized, cross-over design. Blood gases, blood lactate, lung function parameters, maximal inspiratory mouth, sniff nasal and twitch mouth pressures, blood pressure, heart rate, and Borg Dyspnea Scale (BDS) were measured before and after exercise.ResultsThe median drop of PaO2 during walking (2.6mmHg) and stair-climbing (2.4mmHg) was comparable (p=0.93). However, stair-climbing caused more dyspnea (median BDS 6.5 vs. 5.5, p=0.01), a higher median blood lactate (1.1 vs. 0.3mmol/l p<0.001), a more pronounced drop in mean pH (−0.05±0.02 vs. −0.03±0.03, p=0.02) and a higher increase in mean systolic blood pressure (27±11 vs. 13±16mmHg; p=0.009). Stair-climbing, but not walking, caused prolonged lung hyperinflation (mean TLC difference 4.4±4.7% predicted, p=0.003). There was no relationship between the 6-min walking distance (314±104m) and the time needed for stair-climbing (55±33s), nor were there any differences in inspiratory muscle strength and heart rate.ConclusionAlthough the drop of PaO2 was comparable, stair-climbing resulted in more prolonged hyperinflation of the lungs, higher blood lactate production and more dyspnea than walking. The walking distance was not related to the time needed to manage stair-climbing. Therefore, pathophysiological changes during the 6-min walking test do not anticipate those during stair-climbing in patients with severe COPD

P2612Anaemia and renal impairment in heart failure: prevalence and differential prognostic importance according to the AHA ACC heart failure classification

Abstract Background Anaemia (A) and renal impairment (RI) are frequent comorbidities in heart failure (HF) and known to impact adversely on outcome. Purpose In this post-hoc analysis, we allocated HF patients from 4 studies of the Competence Network Heart Failure at baseline to subgroups according to American Heart Association/ American College of Cardiology (AHA/ACC) HF criteria and compared prevalence rates of A and RI at each HF stage and the individual and cumulative long-term impact of these comorbidities on all-cause mortality (ACM) over a 5-year follow-up (FUP) period. Methods To study A and RI prevalence, we performed a cross-sectional analysis in 3344 patients (40.6% female, 65.6±11.2 years, 7.8, 32.3, 38.5, and 21.4% in stages A, B, C1 and C2/D, respectively). FUP data were available for 2496 patients (37.4% female, 66.0±11.3 years, 8.1, 35.3, 32.9, and 23.7% in stages A, B, C1 and C2/D, respectively). A was defined as haemoglobin &lt;13/12 g/dL in men/women and RI as estimated glomerular filtration rate &lt;60 mL/min/1.73m2. Within each HF subgroup, participants were divided in those without these comorbidities (A-/RI-), with either A or RI (A+/RI- and A-/RI+), or with both, A and RI (A+/RI+). For survival analysis log rank tests and multivariable Cox regression models were used. Results Overall prevalence of A in the stages A, B, C1, and C2/D was 3.1, 7.6, 16.5, and 29.8% (p&lt;0.001) and of RI 17.6, 21.3, 24.4, and 46.6% (p&lt;0.001), respectively. In the 4 subgroups, prevalence rates of A-/RI- were 80.2, 74.3, 66.3, and 42.1%, (p&lt;0.001). A+/RI- and A-/RI+ were present in 2.3, 4.4, 9.3, and 11.3% (p&lt;0.001) and 16.8, 18.1, 17.2, and 28.1 (p&lt;0.001). A+/RI+ was found in 0.8, 3.1, 7.1, and 18.5% (p&lt;0.001). Kaplan Meier curves demonstrate the individual and cumulative prognostic impact of A and RI (Figure). Conclusions Our results demonstrate a high prevalence in particular of RI even in asymptomatic HF stages and significant individual and cumulative long-term adverse effects of A and RI across the entire HF continuum. This includes also the clinically asymptomatic HF stages. Both prevalence and the individual and cumulative negative prognostic impact increase with increasing HF severity calling for careful consideration and management of these comorbidities in the frame of holistic HF care. </jats:sec

Prevalence and prognostic impact of chronic kidney disease and anaemia across ACC/AHA precursor and symptomatic heart failure stages

Background The importance of chronic kidney disease (CKD) and anaemia has not been comprehensively studied in asymptomatic patients at risk for heart failure (HF) versus those with symptomatic HF. We analysed the prevalence, characteristics and prognostic impact of both conditions across American College of Cardiology/American Heart Association (ACC/AHA) precursor and HF stages A–D. Methods and results 2496 participants from three non-pharmacological German Competence Network HF studies were categorized by ACC/AHA stage; stage C patients were subdivided into C1 and C2 (corresponding to NYHA classes I/II and III, respectively). Overall, patient distribution was 8.1%/35.3%/32.9% and 23.7% in ACC/AHA stages A/B/C1 and C2/D, respectively. These subgroups were stratified by the absence ( – ) or presence ( +) of CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73m2) and anaemia (haemoglobin in women/men < 12/ < 13 g/dL). The primary outcome was all-cause mortality at 5-year follow-up. Prevalence increased across stages A/B/C1 and C2/D (CKD: 22.3%/23.6%/31.6%/54.7%; anaemia: 3.0%/7.9%/21.7%/33.2%, respectively), with concordant decreases in median eGFR and haemoglobin (all p < 0.001). Across all stages, hazard ratios [95% confidence intervals] for all-cause mortality were 2.1 [1.8–2.6] for CKD + , 1.7 [1.4–2.0] for anaemia, and 3.6 [2.9–4.6] for CKD + /anaemia + (all p < 0.001). Population attributable fractions (PAFs) for 5-year mortality related to CKD and/or anaemia were similar across stages A/B, C1 and C2/D (up to 33.4%, 30.8% and 34.7%, respectively). Conclusions Prevalence and severity of CKD and anaemia increased across ACC/AHA stages. Both conditions were individually and additively associated with increased 5-year mortality risk, with similar PAFs in asymptomatic patients and those with symptomatic HF