TY  - JOUR
A1  - Tütüncü, Serdar
A1  - Olma, Manuel C.
A1  - Kunze, Claudia
A1  - Krämer, Michael
A1  - Dietzel, Joanna
A1  - Schurig, Johannes
A1  - Filser, Paula
A1  - Pfeilschifter, Waltraud
A1  - Hamann, Gerhard F.
A1  - Büttner, Thomas
A1  - Heuschmann, Peter U.
A1  - Kirchhof, Paulus
A1  - Laufs, Ulrich
A1  - Nabavi, Darius G.
A1  - Röther, Joachim
A1  - Thomalla, Götz
A1  - Veltkamp, Roland
A1  - Eckardt, Kai‐Uwe
A1  - Haeusler, Karl Georg
A1  - Endres, Matthias
T1  - Levels and dynamics of estimated glomerular filtration rate and recurrent vascular events and death in patients with minor stroke or transient ischemic attack
JF  - European Journal of Neurology
N2  - Background and purpose
Impaired kidney function is associated with an increased risk of vascular events in acute stroke patients, when assessed by single measurements of estimated glomerular filtration rate (eGFR). It is unknown whether repeated measurements provide additional information for risk prediction.
Methods
The MonDAFIS (Systematic Monitoring for Detection of Atrial Fibrillation in Patients with Acute Ischemic Stroke) study randomly assigned 3465 acute ischemic stroke patients to either standard procedures or an additive Holter electrocardiogram. Baseline eGFR (CKD‐EPI formula) were dichotomized into values of < versus ≥60 ml/min/1.73 m\(^{2}\). eGFR dynamics were classified based on two in‐hospital values as “stable normal” (≥60 ml/min/1.73 m\(^{2}\)), “increasing” (by at least 15% from baseline, second value ≥ 60 ml/min/1.73 m\(^{2}\)), “decreasing” (by at least 15% from baseline of ≥60 ml/min/1.73 m\(^{2}\)), and “stable decreased” (<60 ml/min/1.73 m\(^{2}\)). The composite endpoint (stroke, major bleeding, myocardial infarction, all‐cause death) was assessed after 24 months. We estimated hazard ratios in confounder‐adjusted models.
Results
Estimated glomerular filtration rate at baseline was available in 2947 and a second value in 1623 patients. After adjusting for age, stroke severity, cardiovascular risk factors, and randomization, eGFR < 60 ml/min/1.73 m\(^{2}\) at baseline (hazard ratio [HR] = 2.2, 95% confidence interval [CI] = 1.40–3.54) as well as decreasing (HR = 1.79, 95% CI = 1.07–2.99) and stable decreased eGFR (HR = 1.64, 95% CI = 1.20–2.24) were independently associated with the composite endpoint. In addition, eGFR < 60 ml/min/1.732 at baseline (HR = 3.02, 95% CI = 1.51–6.10) and decreasing eGFR were associated with all‐cause death (HR = 3.12, 95% CI = 1.63–5.98).
Conclusions
In addition to patients with low eGFR levels at baseline, also those with decreasing eGFR have increased risk for vascular events and death; hence, repeated estimates of eGFR might add relevant information to risk prediction.
KW  - kidney function
KW  - prognosis
KW  - stroke
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-287271
VL  - 29
IS  - 9
SP  - 2716
EP  - 2724
ER  - 
TY  - JOUR
A1  - Dammert, Marcel A.
A1  - Brägelmann, Johannes
A1  - Olsen, Rachelle R.
A1  - Böhm, Stefanie
A1  - Monhasery, Niloufar
A1  - Whitney, Christopher P.
A1  - Chalishazar, Milind D.
A1  - Tumbrink, Hannah L.
A1  - Guthrie, Matthew R.
A1  - Klein, Sebastian
A1  - Ireland, Abbie S.
A1  - Ryan, Jeremy
A1  - Schmitt, Anna
A1  - Marx, Annika
A1  - Ozretić, Luka
A1  - Castiglione, Roberta
A1  - Lorenz, Carina
A1  - Jachimowicz, Ron D.
A1  - Wolf, Elmar
A1  - Thomas, Roman K.
A1  - Poirier, John T.
A1  - Büttner, Reinhard
A1  - Sen, Triparna
A1  - Byers, Lauren A.
A1  - Reinhardt, H. Christian
A1  - Letai, Anthony
A1  - Oliver, Trudy G.
A1  - Sos, Martin L.
T1  - MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer
JF  - Nature Communications
N2  - MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.
KW  - genetic engineering
KW  - oncogenes
KW  - small-cell lung cancer
KW  - targeted therapies
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223569
VL  - 10
ER  -