RepoMed (Medizinische Hochschule Hannover)
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LINE-1 hypomethylation in human hepatocellular carcinomas correlates with shorter overall survival and CIMP phenotype
No full textReactivation of interspersed repetitive sequences due to loss of methylation is associated with genomic instability, one of the hallmarks of cancer cells. LINE-1 hypomethylation is a surrogate marker for global methylation loss and is potentially a new diagnostic and prog-nostic biomarker in tumors. However, the correlation of LINE-1 hypomethylation with clinico-pathological parameters and the CpG island methylator phenotype (CIMP) in patients with liver tumors is not yet well defined, particularly in Caucasians who show quite low rates of HCV/HBV infection and a higher incidence of liver steatosis. Therefore, quantitative DNA methylation analysis of LINE-1, RASSF1A, and CCND2 using pyrosequencing was per-formed in human hepatocellular carcinomas (HCC, n = 40), hepatocellular adenoma (HCA, n = 10), focal nodular hyperplasia (FNH, n = 5), and corresponding peritumoral liver tissues as well as healthy liver tissues (n = 5) from Caucasian patients. Methylation results were correlated with histopathological findings and clinical data. We found loss of LINE-1 DNA meth- ylation only in HCC. It correlated significantly with poor survival (log rank test, p = 0.007). Aninverse correlation was found for LINE-1 and RASSF1A DNA methylation levels (r2 = -0.47,p = 0.002). LINE-1 hypomethylation correlated with concurrent RASSF1/CCND2 hypermethylation (Fisher’s exact test, p = 0.02). Both LINE-1 hypomethylation and RASSF1A/CCND2 hypermethylation were not found in benign hepatocellular tumors (HCA and FNH). Our results show that LINE-1 hypomethylation and RASSF1A/CCND2 hypermethylation are epigenetic aberrations specific for the process of malignant liver transformation. In addition, LINE-1 hypomethylation might serve as a future predictive biomarker to identify HCC patients with unfavorable overall survival
Wohin treibt die Sozialpsychiatrie? Erfahrungsberichte und Debattenbeiträge : Sonderband für die Teilnehmenden an der Fachtagung "Segel setzen 2020" des Netwerks Sozialpsychiatrischer Dienste in Deutschland vom 27. bis 28. März 2020 in Hannover
Get PDFDie Rolle der Autophagie bei akuter und chronischer Hepatitis bis hin zur Tumorgenese im Fah-Mausmodell
Get PDFModeling missing binary outcome data while preserving transitivity assumption yielded more credible network meta-analysis results.
Get PDFOBJECTIVES:The objectives of this study were to elaborate on the conceptual evaluation of transitivity assumption in the context of binary missing participant outcome data (MOD) in network meta-analysis (NMA) and to emphasize on the importance of statistical modeling as a mean to address MOD. STUDY DESIGN AND SETTING:We designate the notion of transitivity assumption in the context of binary MOD and indicate scenarios that compromise transitivity in complex networks. We propose a modification of these scenarios that preserves transitivity assumption. Using a published NMA, we indicate the implications of excluding or imputing, rather than modeling MOD, on NMA findings. RESULTS:Arm-specific scenarios for MOD, as commonly applied in conventional meta-analysis, compromise the validity of transitivity assumption in complex networks. The motivating example reveals that imputation of those scenarios yields estimates in the opposite direction for the basic parameters with narrower credible intervals and inflates between-trial variance. Contrariwise, modeling MOD after modification of the scenarios yields robust estimates for the basic parameters but wider credible intervals and reduces between-trial variance. CONCLUSION:Application of arm-specific scenarios for binary MOD requires modification in complex networks to ensure valid transitivity assumption. Analysts should model, rather than exclude or impute MOD, to provide bias-adjusted results
From Paper to Digital Applications of the Pain Drawing: Systematic Review of Methodological Milestones.
No full textBACKGROUND:In a pain drawing (PD), the patient shades or marks painful areas on an illustration of the human body. This simple yet powerful tool captures essential aspects of the subjective pain experience, such as localization, intensity, and distribution of pain, and enables the extraction of meaningful information, such as pain area, widespreadness, and segmental pattern. Starting as a simple pen-on-paper tool, PDs are now sophisticated digital health applications paving the way for many new and exciting basic translational and clinical applications. OBJECTIVE:Grasping the full potential of digital PDs and laying the groundwork for future medical PD apps requires an understanding of the methodological developments that have shaped our current understanding of uses and design. This review presents methodological milestones in the development of both pen-on-paper and digital PDs, thereby offering insight into future possibilities created by the transition from paper to digital. METHODS:We conducted a systematic literature search covering PD acquisition, conception of PDs, PD analysis, and PD visualization. RESULTS:The literature search yielded 435 potentially relevant papers, from which 53 methodological milestones were identified. These milestones include, for example, the grid method to quantify pain area, the pain-frequency maps, and the use of artificial neural networks to facilitate diagnosis. CONCLUSIONS:Digital technologies have had a significant influence on the evolution of PDs, whereas their versatility is leading to ever new applications in the field of medical apps and beyond. In this process, however, there is a clear need for better standardization and a re-evaluation of methodological and technical limitations that no longer apply today
Quantitative magnetic resonance imaging indicates brain tissue alterations in patients after liver transplantation.
Get PDFPURPOSE:To investigate cerebral microstructural alterations in patients treated with calcineurin inhibitors (CNI) after orthotopic liver transplantation (OLT) using quantitative magnetic resonance imaging (qMRI) and a cross-sectional study design. METHODS:Cerebral qMRI was performed in 85 patients in a median 10 years after OLT compared to 31 healthy controls. Patients were treated with different dosages of CNI or with a CNI-free immunosuppression (CNI-free: n = 19; CNI-low: n = 36; CNI-standard: n = 30). T2-, T2*- and T2'- relaxation times, as well as apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in brain gray and white matter by using the regions of interest method. RESULTS:In comparison to controls, patients revealed significantly increased T2, T2*, T2', ADC and reduced FA, predominantly in the frontal white matter, indicating microstructural brain alterations represented by increased free water (increased T2), reduced neuronal metabolism (increased T2') and a lower degree of spatial organization of the nervous fibers (reduced FA). CNI-low and CNI-free patients showed more alterations than CNI-standard patients. Analysis of their history revealed impairment of kidney function while under standard CNI dose suggesting that these patients may be more vulnerable to toxic CNI side-effects. CONCLUSION:Our findings suggest that the individual sensitivity to toxic side effects should be considered when choosing an appropriate immunosuppressive regimen in patients after liver transplantation
E. coli primase and DNA polymerase III holoenzyme are able to bind concurrently to a primed template during DNA replication.
Get PDFDuring DNA replication in E. coli, a switch between DnaG primase and DNA polymerase III holoenzyme (pol III) activities has to occur every time when the synthesis of a new Okazaki fragment starts. As both primase and the χ subunit of pol III interact with the highly conserved C-terminus of single-stranded DNA-binding protein (SSB), it had been proposed that the binding of both proteins to SSB is mutually exclusive. Using a replication system containing the origin of replication of the single-stranded DNA phage G4 (G4ori) saturated with SSB, we tested whether DnaG and pol III can bind concurrently to the primed template. We found that the addition of pol III does not lead to a displacement of primase, but to the formation of higher complexes. Even pol III-mediated primer elongation by one or several DNA nucleotides does not result in the dissociation of DnaG. About 10 nucleotides have to be added in order to displace one of the two primase molecules bound to SSB-saturated G4ori. The concurrent binding of primase and pol III is highly plausible, since even the SSB tetramer situated directly next to the 3'-terminus of the primer provides four C-termini for protein-protein interactions
