Background
Novel biomarkers representing different pathobiological pathways and their role in patients with acute myocardial infarction (AMI) were studied.
Methods
We retrospectively analysed serum ...levels of soluble suppression of tumorigenicity (sST2), growth‐differentiation factor‐15 (GDF‐15), soluble urokinase plasminogen activator receptor (suPAR), heart‐type fatty acid‐binding protein (H‐FABP) and plasma fetuin A in blood of patients with AMI (STEMI, n = 61; NSTEMI, n = 57) compared to controls with excluded coronary artery disease (n = 76). Furthermore, detailed correlation analysis was performed.
Results
Compared with controls, in patients with STEMI and NSTEMI higher levels expressed as median of sST2 in pg/mL (STEMI: 13210·9, NSTEMI: 11989·1, control: 5248; P < 0·001), GDF‐15 in pg/mL (STEMI: 818·8, NSTEMI 677·5, control 548·6; P < 0·001), suPAR in pg/mL (STEMI: 3461·1, NSTEMI: 3466·7, control: 2463·6; P < 0·001), H‐FABP in ng/mL (STEMI: 5·8, NSTEMI: 5·4, control: 0·0; P < 0·001) and lower plasma fetuin A levels in μg/mL (STEMI: 95, NSTEMI: 54, control: 116·6; P < 0·001) were detected. Correlation analysis found clinical and biochemical parameters such as ejection fraction, length of hospital stay, creatine kinase, NT‐proBNP and hs Troponin T levels as well as inflammatory markers (CRP, leucocytes) to be significantly correlated with novel biomarkers.
Conclusion
Plasma levels of novel biomarkers were significantly elevated (sST2, GDF‐15, H‐FABP, suPAR) or inversely downregulated (fetuin A) in patients with AMI compared to a control group with excluded coronary artery disease. Significant correlations with various clinical parameters and standard biochemical markers were found.
Insufficient spatial and temporal resolutions have limited image quality and accuracy of multi-detector CT (MDCT) for coronary artery visualization and detection of stenoses. We assessed the accuracy ...of a new 16-slice scanner with 370 ms rotation and 0.75 mm collimation for detection of coronary stenoses using an analysis approach based on coronary artery segments.
Fifty consecutive patients scheduled for diagnostic coronary angiography in stable clinical condition and sinus rhythm were enrolled. All patients with a heart rate > 60 b.p.m. received 100 mg atenolol p.o. and up to four doses of 5 mg metoprolol i.v. before the scan. MDCT was performed using 16 x 0.75 mm collimation, 120 kV, and ECG-gated tube current modulation. Ninety millilitres of contrast agent was injected intravenously. MDCT images were visually analysed using the 16-segment coronary artery model of the American Heart Association and compared with invasive, quantitative coronary angiography in a blinded fashion. A significant stenosis was assumed if the diameter reduction was > or = 50%. Mean heart rate was 58 b.p.m. during MDCT. After exclusion of two patients with not fully evaluable data sets, MDCT correctly identified at least one coronary stenosis in all 25 patients with significant coronary lesions in angiography and correctly demonstrated the absence of stenoses in 19/23 patients (sensitivity 100%, specificity 83%). Sensitivity and specificity for all 50 patients were 93 and 83%, respectively. On a per-segment basis, nine coronary segments distal of total occlusions and 128 coronary segments with a reference diameter < 1.5 mm were excluded from the analysis. Twenty-eight of the included 663 segments (4%) were unevaluable due to calcification or motion artefact. In the remaining 635 segments, 50/53 stenoses were detected by MDCT (sensitivity 94%, specificity 96%, negative predictive value 99%, positive predictive value 69%).
Increasing temporal and spatial resolutions of MDCT lead to improved evaluation and diagnostic accuracy for detection of coronary stenoses.
Interleukin (IL)-16, a polypeptide cytokine, plays a crucial role in the inflammatory process, acting as a chemoattractant for peripheral immune cells and has been linked to various inflammatory ...diseases. However, its role in patients with acute myocardial infarction (AMI) is unclear.We retrospectively analyzed serum levels of IL-16 in blood of patients with (STEMI, n = 45) and without ST-segment elevation myocardial infarction (NSTEMI, n = 42) compared with controls with excluded coronary artery disease (n = 55). Furthermore, correlation analysis with inflammatory cells, C-reactive protein (CRP) levels, dendritic cell precursors (DCPs), and other clinical and biochemical markers was performed.Compared with controls, patients with STEMI and NSTEMI evidenced higher levels of IL-16 in pg/mL (STEMI: 759.38 ± 471.54, NSTEMI: 677.77 ± 438.8, control: 500.45 ± 432.21; P = .002). IL-16 correlated with CRP (r = 0.26, P = .001), leucocytes (r = 0.38, P < .001), NT-proBNP (r = 0.20, P = .02) and hsTnT (r = 0.25, P = .004). Circulating myeloid DCPs, plasmacytoid DCPs, and total DCPs showed a significant inverse correlation to IL-16 levels (r = -0.21, P = .01; r = -0.23, P = .005; r = -0.26, P = .002, respectively).Interleukin-16 might play an important role in the inflammatory process of patients suffering from AMI and correlates with inflammatory cell activation and clinical and biochemical markers. The cytokine IL-16 might upregulate the proinflammatory response and recruitment of inflammatory cells into infarcted myocardium.
Importance Staphylococcus aureusbacteremia (SAB) is a common and potentially severe infectious disease (ID). Retrospective studies and derived meta-analyses suggest that bedside infectious disease ...consultation (IDC) for SAB is associated with improved survival; however, such IDCs might not always be possible because of the lack of ID specialists, particularly at nonacademic hospitals. Objectives To investigate whether unsolicited telephone IDCs (triggered by an automated blood stream infection reporting system) to nonacademic hospitals improved 30-day all-cause mortality in patients with SAB. Design, Setting, and Participants This patient-blinded, multicenter, interventional, cluster randomized, controlled, crossover clinical trial was conducted in 21 rural, nonacademic hospitals in Thuringia, Germany. From July 1, 2016, to December 31, 2018, 1029 blood culture reports were assessed for eligibility. A total of 386 patients were enrolled, whereas 643 patients were not enrolled for the following reasons: death before enrollment (n = 59); palliative care (n = 41); recurrence of SAB (n = 9); discharge from the hospital before enrollment (n = 77); age younger than 18 years (n = 5); duplicate report from a single patient (n = 26); late report (n = 17); blood culture reported during the washout phase (n = 48); and no signed informed consent for other or unknown reasons (n = 361). Interventions During the ID intervention phase, ID specialists from Jena University Hospital provided unsolicited telephone IDCs to physicians treating patients with SAB. During the control phase, patients were treated according to local standards. Crossover was performed after including 15 patients or, at the latest, 1 year after the first patient was included. Main Outcomes and Measures Thirty-day all-cause mortality. Results A total of 386 patients (median IQR age, 75 63-82 years; 261 67.6% male) were included, with 177 randomized to the IDC group and 209 to the control group. The 30-day all-cause mortality rate did not differ between the IDC and control groups (relative risk reduction RRR, 0.12; 95% CI, −2.17 to 0.76;P = .81). No evidence was found of a difference in secondary outcomes, including 90-day mortality (RRR, 0.17; 95% CI, −0.59 to 0.57;P = .62), 90-day recurrence (RRR, 0.10; 95% CI, −2.51 to 0.89;P = .89), and hospital readmission (RRR, 0.04; 95% CI, −0.63 to 0.48;P = .90). Exploratory evidence suggested that indicators of quality of care were potentially realized more often in the IDC group than in the control group (relative quality improvement, 0.16; 95% CI, 0.08-0.26;P = .01). Conclusions and Relevance In this cluster randomized clinical trial, unsolicited telephone IDC, although potentially enhancing quality of care, did not improve 30-day all-cause mortality in patients with SAB. Trial Registration drks.de Identifier:DRKS00010135
Aims Insufficient spatial and temporal resolutions have limited image quality and accuracy of multi-detector CT (MDCT) for coronary artery visualization and detection of stenoses. We assessed the ...accuracy of a new 16-slice scanner with 370 ms rotation and 0.75 mm collimation for detection of coronary stenoses using an analysis approach based on coronary artery segments. Methods and results Fifty consecutive patients scheduled for diagnostic coronary angiography in stable clinical condition and sinus rhythm were enrolled. All patients with a heart rate >60 b.p.m. received 100 mg atenolol p.o. and up to four doses of 5 mg metoprolol i.v. before the scan. MDCT was performed using 16×0.75 mm collimation, 120 kV, and ECG-gated tube current modulation. Ninety millilitres of contrast agent was injected intravenously. MDCT images were visually analysed using the 16-segment coronary artery model of the American Heart Association and compared with invasive, quantitative coronary angiography in a blinded fashion. A significant stenosis was assumed if the diameter reduction was ≥50%. Mean heart rate was 58 b.p.m. during MDCT. After exclusion of two patients with not fully evaluable data sets, MDCT correctly identified at least one coronary stenosis in all 25 patients with significant coronary lesions in angiography and correctly demonstrated the absence of stenoses in 19/23 patients (sensitivity 100%, specificity 83%). Sensitivity and specificity for all 50 patients were 93 and 83%, respectively. On a per-segment basis, nine coronary segments distal of total occlusions and 128 coronary segments with a reference diameter <1.5 mm were excluded from the analysis. Twenty-eight of the included 663 segments (4%) were unevaluable due to calcification or motion artefact. In the remaining 635 segments, 50/53 stenoses were detected by MDCT (sensitivity 94%, specificity 96%, negative predictive value 99%, positive predictive value 69%). Conclusion Increasing temporal and spatial resolutions of MDCT lead to improved evaluation and diagnostic accuracy for detection of coronary stenoses.
Abstract
The PRoteomics IDEntifications (PRIDE) database (https://www.ebi.ac.uk/pride/) is the world’s largest data repository of mass spectrometry-based proteomics data, and is one of the founding ...members of the global ProteomeXchange (PX) consortium. In this manuscript, we summarize the developments in PRIDE resources and related tools since the previous update manuscript was published in Nucleic Acids Research in 2016. In the last 3 years, public data sharing through PRIDE (as part of PX) has definitely become the norm in the field. In parallel, data re-use of public proteomics data has increased enormously, with multiple applications. We first describe the new architecture of PRIDE Archive, the archival component of PRIDE. PRIDE Archive and the related data submission framework have been further developed to support the increase in submitted data volumes and additional data types. A new scalable and fault tolerant storage backend, Application Programming Interface and web interface have been implemented, as a part of an ongoing process. Additionally, we emphasize the improved support for quantitative proteomics data through the mzTab format. At last, we outline key statistics on the current data contents and volume of downloads, and how PRIDE data are starting to be disseminated to added-value resources including Ensembl, UniProt and Expression Atlas.
Bag-1 is a multifunctional protein that regulates Hsp70 chaperone activity, apoptosis, and proliferation. The three major Bag-1 isoforms have different subcellular localizations and partly ...non-overlapping functions. To identify the detailed interaction network of each isoform, we utilized mass spectrometry-based proteomics and found that interactomes of Bag-1 isoforms contained many common proteins, with variations in their abundances. Bag-1 interactomes were enriched with proteins involved in protein processing and degradation pathways. Novel interaction partners included VCP/p97; a transitional ER ATPase, Rad23B; a shuttling factor for ubiquitinated proteins, proteasome components, and ER-resident proteins, suggesting a role for Bag-1 also in ER-associated protein degradation (ERAD). Bag-1 pull-down from cells and tissues from breast cancer patients validated these interactions and showed cancer-related prominence. Using in silico predictions we detected hotspot residues of Bag-1. Mutations of these residues caused loss of binding to protein quality control elements and impaired proteasomal activity in MCF-7 cells. Following CD147 glycosylation pattern, we showed that Bag-1 downregulated VCP/p97-dependent ERAD. Overall, our data extends the interaction map of Bag-1, and broadens its role in protein homeostasis. Targeting the interaction surfaces revealed in this study might be an effective strategy in the treatment of cancer.
Abstract
Uremic cardiomyopathy is characterized by diastolic dysfunction, left ventricular hypertrophy (LVH), and fibrosis. Dysregulation of the kisspeptin receptor (KISS1R)-mediated pathways are ...associated with the development of fibrosis in cancerous diseases. Here, we investigated the effects of the KISS1R antagonist peptide-234 (P234) on the development of uremic cardiomyopathy. Male Wistar rats (300–350 g) were randomized into four groups: (i) Sham, (ii) chronic kidney disease (CKD) induced by 5/6 nephrectomy, (iii) CKD treated with a lower dose of P234 (
ip.
13 µg/day), (iv) CKD treated with a higher dose of P234 (
ip.
26 µg/day). Treatments were administered daily from week 3 for 10 days. At week 13, the P234 administration did not influence the creatinine clearance and urinary protein excretion. However, the higher dose of P234 led to reduced anterior and posterior wall thicknesses, more severe interstitial fibrosis, and overexpression of genes associated with left ventricular remodeling (
Ctgf, Tgfb, Col3a1, Mmp9
), stretch (
Nppa
), and apoptosis (
Bax, Bcl2, Casp7
) compared to the CKD group. In contrast, no significant differences were found in the expressions of apoptosis-associated proteins between the groups. Our results suggest that the higher dose of P234 hastens the development and pathophysiology of uremic cardiomyopathy by activating the fibrotic TGF-β-mediated pathways.
Erlotinib is approved for the first line treatment of epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer. Since the number of prospective studies in Caucasian ...patients treated in routine clinical setting is limited we conducted a multicenter, phase IV clinical trial to determine the efficacy and safety of erlotinib and to demonstrate the feasibility of the validated standardized companion diagnostic method of EGFR mutation detection.
651 chemonaive, cytologically or histologically verified advanced stage lung adenocarcinoma patients from Hungary, Turkey and Latvia were screened for exon19 microdeletions and exon21 L858R EGFR mutations using the companion diagnostic EGFR test. EGFR mutation-positive, locally advanced or metastatic lung adenocarcinoma patients received as first line treatment erlotinib at 150 mg/day. The primary endpoint was progression-free survival (PFS).
62 EGFR mutation-positive patients (9.5% of screened) were included in the safety/intent-to-treat cohort. Median PFS was 12.8 months (95%CI, 9.9-15.8), objective response rate and one-year survival was 66.1% and 82.5%, respectively. Most frequent treatment related adverse events were diarrhoea and rash. Eastern Oncology Cooperative Group Performance Status (ECOG PS), smoking status and M1a/M1b disease stage were significant prognosticators of PFS (p = 0.017, p = 0.045 and p = 0.002, respectively). There was no significant difference in PFS between the subgroups stratified by gender, age or exon19 vs exon21 mutation.
Our study confirmed the efficacy and safety of first line erlotinib monotherapy in Caucasian patients with locally advanced or metastatic lung adenocarcinoma carrying activating EGFR mutations based on the screening with the approved companion diagnostic procedure.
ClinicalTrials.gov Identifier: NCT01609543.
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