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Background: The association of aspartate aminotransferase to alanine aminotransferase ratio (De Ritis ratio) with clinical outcomes in patients with chronic coronary syndromes (CCS) remains unclear. This study aims to assess the association of De Ritis ratio with adverse cardiovascular events in patients with CCS. Materials and Methods: The study included 5020 patients with CCS undergoing percutaneous coronary intervention. Patients were categorized into groups according to tertiles of the De Ritis ratio: tertile 1 (De Ritis ratio: <.75; n = 1688 patients), tertile 2 (De Ritis ratio:.75–1.08; n = 1666 patients) and tertile 3 (De Ritis ratio: >1.08; n = 1666 patients). The primary endpoint was 3‐year mortality. Results: At 3 years, there were 384 deaths, 176 myocardial infarctions and 61 strokes. In groups with De Ritis in the 1st, 2nd and 3rd tertiles, deaths occurred in 5.0%, 7.5% and 14.5% of the patients, respectively (adjusted hazard ratio = 1.09, 95% confidence interval [1.06–1.12], p <.001); myocardial infarctions occurred in 2.6%, 3.5% and 5.1% of the patients, respectively (p <.001); strokes occurred in 1.0%, 1.2% and 1.9% of the patients, respectively (p =.030); bleeding at 30 days (n = 112) occurred in 1.4%, 1.6% and 3.7% of the patients, respectively (p <.001). The C‐statistic of the Cox proportional hazards model for all‐cause mortality with baseline data without the De Ritis ratio was.815 [.794–.836] and.818 [.797–.838] after the inclusion of the De Ritis ratio (delta C‐statistic =.003; p =.005). Conclusions: In patients with CCS undergoing percutaneous coronary intervention, an elevated De Ritis ratio was associated with long‐term major adverse cardiovascular events. [ABSTRACT FROM AUTHOR]

Background: The association between elevated creatine kinase (CK) and bleeding in patients with acute coronary syndrome (ACS) remains incompletely investigated. We undertook this study to assess whether there is an association between elevated CK activity and the risk for bleeding in contemporary patients with ACS. Materials and Methods: This post hoc analysis of a randomized trial included 3368 patients with ACS undergoing percutaneous coronary intervention. CK was measured serially in all patients until hospital discharge. The main outcome was 30‐day incidence of major bleeding (type 3 to 5 bleeding according to the Bleeding Academic Research Consortium criteria). Results: Patients were categorized in groups according to the peak CK tertiles: 1st tertile (CK ≤259 U/L; n = 1127 patients), 2nd tertile (CK ≥260 to 990 U/L; n = 1119 patients), and 3rd tertile (CK ≥ 991 U/L; n = 1122 patients). Peak CK activity was higher in patients with bleeding than those without bleeding (771 [316‐1845] U/L vs. 496 [190‐1357] U/L; P <.001). Bleeding occurred in 26 patients (2.3%) with peak CK within 1st tertile, 39 patients (3.5%) with peak CK within 2nd tertile, and 54 patients (4.8%) with peak CK within 3rd tertile (univariable hazard ratio [HR]=1.39, 95% confidence interval [CI] 1.08 to 1.81, P =.012, per tertile increment in CK values). After adjustment, peak CK activity remained significantly associated with the 30‐day bleeding (HR = 1.67 [1.16‐2.41]; P =.006 per unit increment in logarithmic CK values). The C statistic of the multivariable model with CK activity was 0.807 [0.770‐0.842]. Conclusions: In patients with ACS, peak CK activity was independently associated with increased 30‐day incidence of bleeding. [ABSTRACT FROM AUTHOR]

Objectives: To identify an appropriate reference gene for the analysis of circulating micro-ribonucleic acid in patients with urological malignancies. Methods: Serum from patients with prostate cancer ( n = 24), bladder cancer ( n = 24), renal cell carcinoma ( n = 24) and control subjects ( n = 48) was spiked with cel-miR-39, and then ribonucleic acid was isolated. Quantitative real-time polymerase chain reaction was used to determine the levels of candidate reference genes ( RNU1-4, RNU6-2, SNORD43, SNORD44, SNORD48, S NORA74A, miR-let-7a-1, miR-106a). Reference gene stability was determined using the NormFinder, geNorm and comparative delta-Ct algorithm. The effect of normalization was tested with miR-21 as the target gene, as this was previously suggested to be upregulated in cancer patients' serum. Results: Recovery of cel-miR-39 (mean 11.6%, range 1-56%) was similar in control subjects and cancer patients. SNORD44 and SNORD74A levels were around the detection limit of the assay and were thus omitted. All remaining candidates showed satisfying stability; SNORD43 was the most stable reference gene using all three algorithms. A combination of two genes ( SNORD43, RNU1-4) increases the stability somewhat. The level of miR-21 was similar in cancer patients and healthy controls, irrespective of the normalization strategy. Conclusions: SNORD43 is a suitable reference gene for the analysis of circulating micro-ribonucleic acid in patients with urological malignancies. Our study questions the suitability of miR-21 as a biomarker for uro-oncological patients. [ABSTRACT FROM AUTHOR]

Nucleosomes, complexes of DNA and histone proteins, are released during cell death into the blood circulation. Elevated serum and plasma levels have been found in various forms of cancer, but also in autoimmune diseases and acute situations such as stroke, trauma, and during sepsis. Here, the clinical relevance of circulating nucleosomes for diagnosis, staging, prognosis, and therapeutic monitoring of cancer is reviewed. Several studies have shown that levels of nucleosomes are significantly higher in serum and plasma of cancer patients in comparison to healthy controls. However, because of elevations of nucleosome levels in patients with benign diseases relevant for differential diagnosis, they are not suitable for cancer diagnosis. Concerning tumor staging, nucleosome levels correlate with tumor stage and presence of metastases in gastrointestinal cancer, but not in other tumor types. Prognostic value of circulating nucleosomes is found in lung cancer in univariate analyses, but not in multivariate analyses. Circulating nucleosomes are most informative for the monitoring of cytotoxic therapy. Strongly decreasing levels are mainly found in patients with remission of disease, whereas constantly high or increasing values are associated with progressive disease during chemo- and radiotherapy. In addition, therapy outcome is already indicated by the nucleosomal course during the first week of chemo- and radiotherapy in patients with lung, pancreatic, and colorectal cancer as well as in hematologic malignancies. Despite their non-tumor-specificity, kinetics of nucleosomes are valuable markers for the early estimation of therapeutic efficacy and may be helpful to adapting early cancer therapy in the future. [ABSTRACT FROM AUTHOR]

This study aimed to test the diagnostic utility of the DNA integrity index for detection of cancer. Matched serum and plasma samples of 42 patients with various forms of cancer and 17 patients with corresponding benign diseases were analyzed. DNA was isolated from 1 mL serum and plasma using the MagNA Pure LC system. Cell-free DNA was quantified by real-time PCR using the reference gene of the LightCycler t(14;18) kit. Subsequently, the DNA integrity index was calculated as the ratio in relative abundance of 347-bp versus 137-bp PCR products. We found that DNA concentrations were not different in plasma (median: 4.5 ng/mL) and serum (67.1 ng/mL) of patients with benign diseases when compared with values in plasma (5.1 ng/mL) and serum (65.4 ng/mL) of cancer patients. Similarly, the DNA integrity index in plasma (0.38), and serum of patients with benign diseases (0.29) was comparable to values in plasma (0.33) and serum (0.37) of cancer patients. Diagnostic sensitivity of DNA (AUC 0.53) and DNA integrity (AUC 0.45) was poor in plasma, and was increased only slightly by the combination of both (AUC 0.57). In serum, sensitivity of DNA (AUC 0.52) and DNA integrity (AUC 0.64) was higher and was further improved by the combination of both (AUC 0.72) reaching a sensitivity of 30% at 100% specificity. In conclusion, we could not confirm a high diagnostic utility of the DNA integrity index. However, a combination with other markers such as DNA may enhance sensitivity for cancer detection. [ABSTRACT FROM AUTHOR]

Facing an era of promising new antitumor therapies, predictors of therapy response are needed for the individual management of treatment. In sera collected prospectively from 311 patients with advanced non-small cell lung cancer receiving first-line chemotherapy, changes in nucleosomal DNA fragments, cytokeratin-19 fragments (CYFRA 21–1), carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and progastrin-releasing peptide (ProGRP) were investigated and correlated with therapy response. In univariate analysis, high levels, slower and incomplete decline in nucleosomal DNA, CYFRA 21–1, and CEA predicted poor outcome. DNA concentrations at day 8 of the first therapeutic cycle and CYFRA 21–1 before start of the second cycle were identified as best predictive variables. In multivariate analysis, they predicted progression with a specificity of 100% in 29% of the cases earlier than imaging techniques. Thus, nucleosomal DNA and CYFRA 21–1 specifically identify a subgroup of patients with insufficient therapy response at the early treatment phase and showed to be valuable for disease management. [ABSTRACT FROM AUTHOR]

The inadequate response of immune cells to circulating apoptotic products, such as nucleosomal DNA fragments, is assumed to be a potent stimulus for the production of autoantibodies during the pathogenesis and progression of systemic lupus erythematosus (SLE). Here, we analyzed the levels of circulating nucleosomes, caspases, and C-reactive protein in sera of 244 individuals with various autoimmune diseases (155 with autoimmune hepatic disorders, 25 with ANCA-associated vasculitis, and 64 with various connective tissue diseases), and 32 healthy controls. Nucleosomes and caspase activities were significantly elevated in sera of patients with hepatic autoimmune diseases, connective tissue diseases, and particularly in ANCA-associated vasculitis when compared with healthy individuals. Nucleosomes showed a correlation with caspases, and caspases with C-reactive protein, but nucleosomes did not correlate with C-reactive protein. Serum levels of the apoptotic products, nucleosomes, and caspases are increased in various autoimmune diseases but may not be solely responsible for antinucleosome antibody production in SLE patients. It remains to be clarified whether qualitative changes in nucleosomes are linked with pathogenesis and disease progression in SLE. [ABSTRACT FROM AUTHOR]

Background: The association between hypocholesterolaemia and outcome of patients with coronary artery disease (CAD) remains controversial. We undertook this study to investigate whether there is an association between spontaneous or under statin therapy occurring hypocholesterolaemia and mortality in patients with CAD. Materials and Methods: This study included 14 952 patients with CAD undergoing percutaneous coronary intervention (PCI). Hypocholesterolaemia was defined as a total cholesterol (TC) <157 mg/dL (the upper limit of 1st quintile of TC). The study outcome was all‐cause mortality at 30 days and 3 years after PCI. Results: Patients are categorized in four groups according to TC and statin therapy on admission: statin‐naïve patients with hypocholesterolaemia (n = 1102), statin‐naïve patients without hypocholesterolaemia (n = 7490), statin‐treated patients with hypocholesterolaemia (n = 1824) and statin‐treated patients without hypocholesterolaemia (n = 4536). In these groups, 30‐day all‐cause deaths occurred in 3.7%, 1.4%, 1.2% and 0.6% of the patients, respectively; 3‐year deaths occurred in 18.0%, 8.4%, 10.9% and 7.2%, of the patients, respectively. After adjustment, hypocholesterolaemia remained independently associated with 30‐day (adjusted hazard ratio [HR] = 1.50, 95% confidence interval [CI] 1.07 to 2.09; P < 0001) and 3‐year (HR = 1.29 [1.12‐1.47]; P <.001) mortality. Statin therapy on admission was independently associated with 30‐day (HR = 0.61 [0.43‐0.86]; P =.012) and 3‐year (HR = 0.82 [0.72‐0.94]; P =.017) mortality with no statin‐by‐cholesterol interaction with respect to 30‐day (adjusted Pint = 0.669) or 3‐year (adjusted Pint = 0.767) all‐cause mortality suggesting that statins reduce the risk of mortality irrespective of cholesterol level. Conclusions: In patients with CAD, hypocholesterolaemia on admission was independently associated with increased risk of all‐cause mortality at 30 days and 3 years after PCI. [ABSTRACT FROM AUTHOR]

Intense physical exercise is known to increase cardiac biomarkers; however, it is unclear, whether this phenomenon is physiological, or if it indicates myocardial tissue injury. The aim of our study was to investigate the effects of seven consecutive days of excessive endurance exercise on continuous assessment of cardiac biomarkers, function, and tissue injury. During a 7‐day trail‐running competition (Transalpine Run, distance 267.4 km, altitude ascent/descent 15556/14450 m), daily blood samples were obtained for cardiac biomarkers (hs‐TnT, NT‐proBNP, and suppression of tumorigenicity‐2 protein (ST2)) at baseline, after each stage and 24–48 h post‐race. In addition, echocardiography was performed every second day, cardiac magnetic resonance imaging (CMR) before (n = 7) and after (n = 16) the race. Twelve (eight males) out of 17 healthy athletes finished all seven stages (average total finish time: 43 ± 8 h). Only NT‐proBNP increased significantly (3.6‐fold, p = 0.009) during the first stage and continued to increase during the race. Hs‐TnT revealed an incremental trend during the first day (2.7‐fold increase, p = 0.098) and remained within the pathological range throughout the race. ST2 levels did not change during the race. All cardiac biomarkers completely returned to physiological levels post‐race. NT‐proBNP kinetics correlated significantly with mild transient reductions in right ventricular function (assessed by TAPSE, tricuspid annular plane systolic function; r = −0.716; p = 0.014). No significant echocardiographic changes in LV dimensions, LV function, or relevant alterations in CMR were observed post‐race. In summary, this study shows that prolonged, repetitive, high‐volume exercise induced a transient, significant increase in NT‐proBNP associated with right ventricular dysfunction without corresponding left ventricular functional or structural impairment. [ABSTRACT FROM AUTHOR]

Paclitaxel/platinum chemotherapy, the backbone of standard first‐line treatment of advanced non‐small cell lung cancer (NSCLC), exhibits high interpatient variability in treatment response and high toxicity burden. Baseline blood biomarker concentrations and tumor size (sum of diameters) at week 8 relative to baseline (RS8) are widely investigated prognostic factors. However, joint analysis of data on demographic/clinical characteristics, blood biomarker levels, and chemotherapy exposure‐driven early tumor response for improved prediction of overall survival (OS) is clinically not established. We developed a Weibull time‐to‐event model to predict OS, leveraging data from 365 patients receiving paclitaxel/platinum combination chemotherapy once every three weeks for ≤six cycles. A developed tumor growth inhibition model, combining linear tumor growth and first‐order paclitaxel area under the concentration‐time curve‐induced tumor decay, was used to derive individual RS8. The median model‐derived RS8 in all patients was a 20.0% tumor size reduction (range from −78% to +15%). Whereas baseline carcinoembryonic antigen, cytokeratin fragments, and thyroid stimulating hormone levels were not significantly associated with OS in a subset of 221 patients, and lactate dehydrogenase, interleukin‐6 and neutrophil‐to‐lymphocyte ratio levels were significant only in univariate analyses (p value < 0.05); C‐reactive protein (CRP) in combination with RS8 most significantly affected OS (p value < 0.01). Compared to the median population OS of 11.3 months, OS was 128% longer at the 5th percentile levels of both covariates and 60% shorter at their 95th percentiles levels. The combined paclitaxel exposure‐driven RS8 and baseline blood CRP concentrations enables early individual prognostic predictions for different paclitaxel dosing regimens, forming the basis for treatment decision and optimizing paclitaxel/platinum‐based advanced NSCLC chemotherapy. [ABSTRACT FROM AUTHOR]

Background: The prognostic value of in‐hospital haemoglobin drop in patients with acute coronary syndrome (ACS) undergoing invasive therapy remains insufficiently investigated. Materials and Methods: This observational study included 3838 patients with ACS with admission and in‐hospital nadir haemoglobin values available. Haemoglobin drop was defined as a positive difference between admission and nadir haemoglobin values. The primary endpoint was one‐year all‐cause mortality. Results: In‐hospital haemoglobin drop occurred in 3142 patients (82%). Patients were categorized into 4 groups: no haemoglobin drop (n = 696 patients), <3 g/dl haemoglobin drop (n = 2703 patients), 3 to <5 g/dl haemoglobin drop (n = 344 patients) and ≥5 g/dl haemoglobin drop (n = 95 patients). The primary endpoint occurred in 156 patients: 17 patients (2.5%) in the group with no haemoglobin drop, 81 patients (3.0%) in the group with <3g/dl haemoglobin drop, 37 patients (10.9%) in the group with 3 to <5 g/dl haemoglobin drop and 21 patients (22.2%) in the group with ≥5 g/dl haemoglobin (adjusted hazard ratio [HR] = 1.30, 95% confidence interval 1.17 to 1.45; p <.001 for one g/dl haemoglobin drop). The association of haemoglobin drop with one‐year mortality remained significant after exclusion of patients with in‐hospital overt bleeding (adjusted HR = 1.27 [1.11–1.46]; p <.001 for one g/dl haemoglobin drop). The lowest haemoglobin drop associated with mortality was 1.23 g/dl in all patients (HR = 1.03 [1.02–1.04]) and 1.13 g/dl in patients without overt bleeding (HR = 1.03 [1.01–1.04]). Conclusions: In patients with ACS, in‐hospital haemoglobin drop was associated with higher risk of one‐year mortality even in the absence of overt bleeding. [ABSTRACT FROM AUTHOR]

Background and Purpose: Irinotecan, used in colorectal cancer therapy, is metabolized by glucuronidation involving different UDP-glucuronosyltransferase (UGT)1A isoforms leading to facilitated elimination from the body. Individuals homozygous for the genetic variants UGT1A1*28 (Gilbert syndrome) and UGT1A7*3 are more susceptible to irinotecan side effects, severe diarrhoea and leukopenia. The aim of this study was to investigate the protective effects and active constituents of coffee during irinotecan therapy using humanized transgenic (htg)UGT1A-WT and htgUGT1A-SNP (carry UGT1A1*28 and UGT1A7*3 polymorphisms) mice.Experimental Approach: HtgUGT1A mice were pretreated with coffee or caffeic acid (CA) + caffeic acid phenylethyl ester (CAPE) and injected with irinotecan. The effects of coffee and CA + CAPE were investigated using reporter gene assays, immunoblot, TaqMan-PCR, siRNA analyses and blood counts.Key Results: Only the combination of the two coffee ingredients, CA and CAPE, mediates protective effects of coffee in a model of irinotecan toxicity by activation of UGT1A genes. Coffee and CA + CAPE significantly increased UGT1A expression and activity along with SN-38 glucuronide excretion in irinotecan-injected htgUGT1A mice, resulting in significant improvement of leukopenia, intestinal oxidative stress and inflammation.Conclusion and Implications: In this study, we identify the compounds responsible for mediating the previously reported coffee-induced activation of UGT1A gene expression. CA and CAPE represent key factors for the protective properties of coffee which are capable of reducing irinotecan toxicity, exerting antioxidant and protective effects. Provided that CA + CAPE do not affect irinotecan efficacy, they might represent a novel strategy for the treatment of irinotecan toxicity. [ABSTRACT FROM AUTHOR]

Summary: Objective: Generalized convulsive seizures (GCS) are associated with high demands on the cardiovascular system, thereby facilitating cardiac complications. To investigate occurrence, influencing factors, and extent of cardiac stress or injury, the alterations and time course of the latest generation of cardiac blood markers were investigated after documented GCS. Methods: Adult patients with refractory epilepsy who underwent video–electroencephalography (EEG) monitoring along with simultaneous one‐lead electrocardiography (ECG) recordings were included. Cardiac biomarkers (cardiac troponin I [cTNI]; high‐sensitive troponin T [hsTNT]; N‐terminal prohormone of brain natriuretic peptide [NT‐proBNP]; copeptin; suppression of tumorigenicity‐2 [SST‐2]; growth differentiation factor 15, [GDF‐15]; soluble urokinase plasminogen activator receptor [suPAR]; and heart‐type fatty acid binding protein [HFABP]) and catecholamines were measured at inclusion and at different time points after GCS. Periictal cardiac properties were assessed by analyzing heart rate (HR), HR variability (HRV), and corrected QT intervals(QTc). Results: Thirty‐six GCS (6 generalized‐onset tonic–clonic seizures and 30 focal to bilateral tonic–clonic seizures) were recorded in 30 patients without a history of cardiac or renal disease. Postictal catecholamine levels were elevated more than twofold. A concomitant increase in HR and QTc, as well as a decrease in HRV, was observed. Elevations of cTNI and hsTNT were found in 3 of 30 patients (10%) and 6 of 23 patients (26%), respectively, which were associated with higher dopamine levels. Copeptin was increased considerably after most GCS, whereas SST‐2, HFABP, and GDF‐15 displayed only subtle variations, and suPAR was unaltered in the postictal period. Cardiac symptoms did not occur in any patient. Significance: The use of more sensitive biomarkers such as hsTNT suggests that signs of cardiac stress occur in about 25% of the patients with GCS without apparent clinical symptoms. SuPAR may indicate clinically relevant troponin elevations. Copeptin could help to diagnose GCS, but specificity needs to be tested. [ABSTRACT FROM AUTHOR]

Aim Hepatic apoptosis is involved in the pathogenesis of immune-mediated liver diseases such as autoimmune hepatitis ( AIH), primary biliary cirrhosis ( PBC) and primary sclerosing cholangitis ( PSC). The aim of our study was to quantify distinct markers of apoptosis in sera of patients with AIH, PBC and PSC, and to evaluate correlation with markers of disease activity and prognosis. Methods Sera of patients with AIH, PBC and PSC, and of healthy controls were collected and distinct cell death markers were quantified using a bead-based multiplex enzyme linked immunosorbent assay (soluble intracellular adhesion molecule [ sICAM], macrophage migration inhibitory factor [ MIF], soluble Fas [s Fas], plasminogen activator inhibitor 1 [ PAI-1]) or single enzyme-linked immunosorbent assays ( DNAse, M30, M65). Results In comparison with healthy controls, the apoptotic markers sFas, sICAM (only in PSC patients), M30 and the cell death marker M65 were substantially elevated in sera of patients with immune-mediated liver diseases, whereas DNAse activity was reduced. Interestingly, patients with advanced PSC presented with higher levels of sICAM, M30 and M65 than patients with mild PSC. Regression analysis revealed correlations between serum levels of sICAM, M30 and M65 with the Mayo Risk Score for PSC, and of M65 with the Mayo Risk Score for PBC. Conclusion Concentrations of the serum markers of apoptosis sFas and M30 and of the marker of total cell death M65 are elevated in patients with immune-mediated liver diseases, whereas activity of DNAse is reduced. In patients with PSC, sICAM, M30 and M65 may serve as indicators for disease activity and prognosis. [ABSTRACT FROM AUTHOR]