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BACKGROUND: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks.
RESULTS: We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and β-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, β-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired.
CONCLUSIONS: Together, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted β-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities.
Introduction: MDRO-colonization has been shown to impair survival in patients with hematological malignancies and solid tumors as well as in patients with liver disease. Despite the increasing spread of multidrug-resistant organisms (MDRO), its impact on patients with hepatocellular carcinoma (HCC) has not been studied. We conducted this retrospective study to analyze the impact of MDRO-colonization on overall prognosis in HCC patients.
Materials and methods: All patients with confirmed HCC diagnosed between January 2008 and December 2017 at the University Hospital Frankfurt were included in this study. HCC patients with a positive MDRO screening before or within the first 90 days after diagnosis of HCC were defined as colonized HCC patients, HCC patients with a negative MDRO screening were defined as noncolonized HCC patients.
Results: 59 (6%) colonized and 895 (94%) noncolonized HCC patients were included. Enterobacterales with extended-spectrum β-lactamase-like phenotype with or without resistance to fluoroquinolones (ESBL/ ± FQ) were the most frequently found MDRO with 59%, followed by vancomycin-resistant Enterococcus faecium with 37%. Colonized HCC patients had more severe cirrhosis and more advanced HCC stage compared to noncolonized HCC patients. Colonized HCC patients showed an impaired survival with a median OS of 189 days (6.3 months) compared to a median OS of 1001 days (33.4 months) in noncolonized HCC patients. MDRO-colonization was identified as an independent risk factor associated with survival in multivariate analysis.
Conclusion: MDRO-colonization is an independent risk factor for survival in patients with HCC highlighting the importance of regular MDRO screening, isolation measures as well as interdisciplinary antibiotic steward-ship programs to guide responsible use of antibiotic agents.
Background The inhibitor telaprevir (VX-950) of the hepatitis C virus (HCV) protease NS3-4A has been tested in a recent phase 1b clinical trial in patients infected with HCV genotype 1. This trial revealed residue mutations that confer varying degrees of drug resistance. In particular, two protease positions with the mutations V36A/G/L/M and T54A/S were associated with low to medium levels of drug resistance during viral breakthrough, together with only an intermediate reduction of viral replication fitness. These mutations are located in the protein interior and far away from the ligand binding pocket. Results Based on the available experimental structures of NS3-4A, we analyze the binding mode of different ligands. We also investigate the binding mode of VX-950 by protein-ligand docking. A network of non-covalent interactions between amino acids of the protease structure and the interacting ligands is analyzed to discover possible mechanisms of drug resistance. We describe the potential impact of V36 and T54 mutants on the side chain and backbone conformations and on the non-covalent residue interactions. We propose possible explanations for their effects on the antiviral efficacy of drugs and viral fitness. Molecular dynamics simulations of T54A/S mutants and rotamer analysis of V36A/G/L/M side chains support our interpretations. Experimental data using an HCV V36G replicon assay corroborate our findings. Conclusion T54 mutants are expected to interfere with the catalytic triad and with the ligand binding site of the protease. Thus, the T54 mutants are assumed to affect the viral replication efficacy to a larger degree than V36 mutants. Mutations at V36 and/or T54 result in impaired interaction of the protease residues with the VX-950 cyclopropyl group, which explains the development of viral breakthrough variants.
Epigenetic neural glioblastoma enhances synaptic integration and predicts therapeutic vulnerability
(2023)
Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is nascent. We present an epigenetically defined neural signature of glioblastoma that independently affects patients survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals high abundance of stem cell-like malignant cells classified as oligodendrocyte precursor and neural precursor cell-like in high-neural glioblastoma. High-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature associates with decreased survival as well as increased functional connectivity and can be detected via DNA analytes and brain-derived neurotrophic factor in plasma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant.
Background: Patients with chronic kidney disease (CKD) are at high risk of myocardial infarction. Cardiac troponins are the biomarkers of choice for the diagnosis of acute myocardial infarction (AMI) without ST‐segment elevation (NSTE). In patients with CKD, troponin levels are often chronically elevated, which reduces their diagnostic utility when NSTE‐AMI is suspected. The aim of this study was to derive a diagnostic algorithm for serial troponin measurements in patients with CKD and suspected NSTE‐AMI.
Methods and Results: Two cohorts, 1494 patients from a prospective cohort study with high‐sensitivity troponin I (hs‐cTnI) measurements and 7059 cases from a clinical registry with high‐sensitivity troponin T (hs‐cTnT ) measurements, were analyzed. The prospective cohort comprised 280 CKD patients (estimated glomerular filtration rate <60 mL/min/1.73 m2). The registry data set contained 1581 CKD patients. In both cohorts, CKD patients were more likely to have adjudicated NSTE‐AMI than non‐CKD patients. The specificities of hs‐cTnI and hs‐cTnT to detect NSTE‐AMI were reduced with CKD (0.82 versus 0.91 for hs‐cTnI and 0.26 versus 0.73 for hs‐cTnT) but could be restored by applying optimized cutoffs to either the first or a second measurement after 3 hours. The best diagnostic performance was achieved with an algorithm that incorporates serial measurements and rules in or out AMI in 69% (hs‐cTnI) and 55% (hs‐cTnT) of CKD patients.
Conclusions: The diagnostic performance of high‐sensitivity cardiac troponins in patients with CKD with suspected NSTE‐AMI is improved by use of an algorithm based on admission troponin and dynamic changes in troponin concentration.
Background: Treatment of patients presenting with possible acute myocardial infarction (AMI) is based on timely diagnosis and proper risk stratification aided by biomarkers. We aimed at evaluating the predictive value of GDF-15 in patients presenting with symptoms suggestive of AMI.
Methods: Consecutive patients presenting with suspected AMI were enrolled in three study centers. Cardiovascular events were assessed during a follow-up period of 6 months with a combined endpoint of death or MI.
Results: From the 1818 enrolled patients (m/f = 1208/610), 413 (22.7%) had an acute MI and 63 patients reached the combined endpoint. Patients with MI and patients with adverse outcome had higher GDF-15 levels compared with non-MI patients (967.1pg/mL vs. 692.2 pg/L, p<0.001) and with event-free patients (1660 pg/mL vs. 756.6 pg/L, p<0.001). GDF-15 levels were lower in patients with SYNTAX score ≤ 22 (797.3 pg/mL vs. 947.2 pg/L, p = 0.036). Increased GDF-15 levels on admission were associated with a hazard ratio of 2.1 for death or MI (95%CI: 1.67–2.65, p<0.001) in a model adjusted for age and sex and of 1.57 (1.13–2.19, p = 0.008) adjusted for the GRACE score variables. GDF-15 showed a relevant reclassification with regards to the GRACE score with an overall net reclassification index (NRI) of 12.5% and an integrated discrimination improvement (IDI) of 14.56% (p = 0.006).
Conclusion: GDF-15 is an independent predictor of future cardiovascular events in patients presenting with suspected MI. GDF-15 levels correlate with the severity of CAD and can identify and risk-stratify patients who need coronary revascularization.
The use of cardiac troponins (cTn) is the gold standard for diagnosing myocardial infarction. Independent of myocardial infarction (MI), however, sex, age and kidney function affect cTn levels. Here we developed a method to adjust cTnI levels for age, sex, and renal function, maintaining a unified cut-off value such as the 99th percentile. A total of 4587 individuals enrolled in a prospective longitudinal study were used to develop a model for adjustment of cTn. cTnI levels correlated with age and estimated glomerular filtration rate (eGFR) in males/females with rage = 0.436/0.518 and with reGFR = −0.142/−0.207. For adjustment, these variables served as covariates in a linear regression model with cTnI as dependent variable. This adjustment model was then applied to a real-world cohort of 1789 patients with suspected acute MI (AMI) (N = 407). Adjusting cTnI showed no relevant loss of diagnostic information, as evidenced by comparable areas under the receiver operator characteristic curves, to identify AMI in males and females for adjusted and unadjusted cTnI. In specific patients groups such as in elderly females, adjusting cTnI improved specificity for AMI compared with unadjusted cTnI. Specificity was also improved in patients with renal dysfunction by using the adjusted cTnI values. Thus, the adjustments improved the diagnostic ability of cTnI to identify AMI in elderly patients and in patients with renal dysfunction. Interpretation of cTnI values in complex emergency cases is facilitated by our method, which maintains a single diagnostic cut-off value in all patients.
Background: Common ECG criteria such as ST-segment changes are of limited value in patients with suspected acute myocardial infarction (AMI) and bundle branch block or wide QRS complex. A large proportion of these patients do not suffer from an AMI, whereas those with ST-elevation myocardial infarction (STEMI) equivalent AMI benefit from an aggressive treatment. Aim of the present study was to evaluate the diagnostic information of cardiac troponin I (cTnI) in hemodynamically stable patients with wide QRS complex and suspected AMI.
Methods: In 417 out of 1818 patients presenting consecutively between 01/2007 and 12/2008 in a prospective multicenter observational study with suspected AMI a prolonged QRS duration was observed. Of these, n = 117 showed significant obstructive coronary artery disease (CAD) used as diagnostic outcome variable. cTnI was determined at admission.
Results: Patients with significant CAD had higher cTnI levels compared to individuals without (median 250ng/L vs. 11ng/L; p<0.01). To identify patients needing a coronary intervention, cTnI yielded an area under the receiver operator characteristics curve of 0.849. Optimized cut-offs with respect to a sensitivity driven rule-out and specificity driven rule-in strategy were established (40ng/L/96ng/L). Application of the specificity optimized cut-off value led to a positive predictive value of 71% compared to 59% if using the 99th percentile cut-off. The sensitivity optimized cut-off value was associated with a negative predictive value of 93% compared to 89% provided by application of the 99th percentile threshold.
Conclusion: cTnI determined in hemodynamically stable patients with suspected AMI and wide QRS complex using optimized diagnostic thresholds improves rule-in and rule-out with respect to presence of a significant obstructive CAD.
Background: The introduction of modern troponin assays has facilitated diagnosis of acute myocardial infarction due to improved sensitivity with corresponding loss of specificity. Atrial fibrillation (AF) is associated with elevated levels of troponin. The aim of the present study was to evaluate the diagnostic performance of troponin I in patients with suspected acute coronary syndrome and chronic AF.
Methods: Contemporary sensitive troponin I was assayed in a derivation cohort of 90 patients with suspected acute coronary syndrome and chronic AF to establish diagnostic cut-offs. These thresholds were validated in an independent cohort of 314 patients with suspected myocardial infarction and AF upon presentation. Additionally, changes in troponin I concentration within 3 hours were used.
Results: In the derivation cohort, optimized thresholds with respect to a rule-out strategy with high sensitivity and a rule-in strategy with high specificity were established. In the validation cohort, application of the rule-out cut-off led to a negative predictive value of 97 %. The rule-in cut-off was associated with a positive predictive value of 88 % compared with 71 % if using the 99th percentile cut-off. In patients with troponin I levels above the specificity-optimized threshold, additional use of the 3-hour change in absolute/relative concentration resulted in a further improved positive predictive value of 96 %/100 %.
Conclusions: Troponin I concentration and the 3-hour change in its concentration provide valid diagnostic information in patients with suspected myocardial infarction and chronic AF. With regard to AF-associated elevation of troponin levels, application of diagnostic cut-offs other than the 99th percentile might be beneficial.
Background: Autotaxin (ATX) and its product lysophosphatidic acid (LPA) are considered to be involved in the development of liver fibrosis and elevated levels of serum ATX have been found in patients with hepatitis C virus associated liver fibrosis. However, the clinical role of systemic ATX in the stages of liver cirrhosis was unknown. Here we investigated the relation of ATX serum levels and severity of cirrhosis as well as prognosis of cirrhotic patients.
Methods: Patients with liver cirrhosis were prospectively enrolled and followed until death, liver transplantation or last contact. Blood samples drawn at the day of inclusion in the study were assessed for ATX content by an enzyme-linked immunosorbent assay. ATX levels were correlated with the stage as well as complications of cirrhosis. The prognostic value of ATX was investigated by uni- and multivariate Cox regression analyses. LPA concentration was determined by liquid chromatography-tandem mass spectrometry.
Results: 270 patients were enrolled. Subjects with liver cirrhosis showed elevated serum levels of ATX as compared to healthy subjects (0.814±0.42 mg/l vs. 0.258±0.40 mg/l, P<0.001). Serum ATX levels correlated with the Child-Pugh stage and the MELD (model of end stage liver disease) score and LPA levels (r = 0.493, P = 0.027). Patients with hepatic encephalopathy (P = 0.006), esophageal varices (P = 0.002) and portal hypertensive gastropathy (P = 0.008) had higher ATX levels than patients without these complications. Low ATX levels were a parameter independently associated with longer overall survival (hazard ratio 0.575, 95% confidence interval 0.365–0.905, P = 0.017).
Conclusion: Serum ATX is an indicator for the severity of liver disease and the prognosis of cirrhotic patients.