Early Everolimus-Facilitated Reduced Tacrolimus in Liver Transplantation: Results From the Randomized HEPHAISTOS Trial.

Everolimus-facilitated reduced-exposure tacrolimus (EVR + rTAC) at 30 days after liver transplantation (LT) has shown advantages in renal preservation. This study evaluated the effects of early initiation of EVR + rTAC in de novo LT recipients (LTRs). In HEPHAISTOS (NCT01551212, EudraCT 2011-003118-17), a 12-month, multicenter, controlled study, LTRs were randomly assigned at 7 to 21 days after LT to receive EVR + rTAC or standard-exposure tacrolimus (sTAC) with steroids.

The prevalence of cirrhotic cardiomyopathy according to different diagnostic criteria.

Background And Aims: Recently published criteria by 2019 Cirrhotic Cardiomyopathy Consortium set a lower threshold for reduced ejection fraction to diagnose systolic dysfunction in cirrhotic patients, and stress testing was replaced by echocardiography strain imaging. The criteria to diagnose diastolic dysfunction are in general concordant with the 2016 ASE/EACVI guidelines and differ considerably from the 2005 Montreal recommendations. We aimed to assess the prevalence of cirrhotic cardiomyopathy according to different diagnostic criteria.

Factors influencing agreement of breast cancer luminal molecular subtype by Ki67 labeling index between core needle biopsy and surgical resection specimens.

Reliable determination of Ki67 labeling index (Ki67-LI) on core needle biopsy (CNB) is essential for determining breast cancer molecular subtype for therapy planning. However, studies on agreement between molecular subtype and Ki67-LI between CNB and surgical resection (SR) specimens are conflicting. The present study analyzed the influence of clinicopathological and sampling-associated factors on agreement.

Toward harmonizing prospective effectiveness assessment for road safety: Comparing tools in standard test case simulations.

With the overall goal to harmonize prospective effectiveness assessment of active safety systems, the specific objective of this study is to identify and evaluate sources of variation in virtual precrash simulations and to suggest topics for harmonization resulting in increased comparability and thus trustworthiness of virtual simulation-based prospective effectiveness assessment. A round-robin assessment of the effectiveness of advanced driver assistance systems was performed using an array of state-of-the-art virtual simulation tools on a set of standard test cases. The results were analyzed to examine reasons for deviations in order to identify and assess aspects that need to be harmonized and standardized.

[Medical care situation of patients with ankylosing spondylitis and psoriatic arthritis in Germany : Medical care situation of patients with spondyloarthritis (SpA): ankylosing spondylitis (AS) and psoriatic arthritis (PsA) from the perspective of rheumatologists in private practice and hospitals in Germany-Results of the research project "SpA Loop-Life of Outpatients"].

Background: The prevalence of spondyloarthritis (SpA) in Germany is approximately 1-1.4% and includes predominantly axial SpA (axSpA) and predominantly peripheral SpA. Ankylosing spondylitis (AS) belongs to the group of axial SpA but also exhibits peripheral manifestations.

Long-term follow-up of five yr shows superior renal function with everolimus plus early calcineurin inhibitor withdrawal in the PROTECT randomized liver transplantation study.

Background: The 12-month (M) PROTECT study showed that de novo liver transplant recipients (LTxR) who switched from a calcineurin inhibitor (CNI)-based immunosuppression to a CNI-free everolimus (EVR)-based regimen showed numerically better renal function. Here, we present the five-yr follow-up data.

Methods: PROTECT was a randomized controlled study in which LTxR received basiliximab and CNI-based immunosuppression ± corticosteroids.

Early conversion from cyclosporine to everolimus following living-donor kidney transplantation: outcomes at 5 years posttransplant in the randomized ZEUS trial.

Aims: To assess 5-year efficacy, renal, and safety outcomes following early conversion from cyclosporine to everolimus vs. a standard cyclosporine-based regimen in living-donor kidney transplant (LDKT) recipients.

Materials And Methods: The ZEUS study was a randomized, open-label, 1-year, multicenter study in which 300 de novo kidney transplant recipients continued to receive cyclosporine or converted to everolimus at 4.

Sp100A is a tumor suppressor that activates p53-dependent transcription and counteracts E1A/E1B-55K-mediated transformation.

Human adenoviruses (HAdV) are used as a model system to investigate tumorigenic processes in mammalian cells where the viral oncoproteins E1A and E1B-55K are absolutely required for oncogenic transformation, because they simultaneously accelerate cell cycle progression and inhibit tumor suppressor proteins such as p53, although the underlying mechanism is still not understood in detail. In our present study, we provide evidence that E1B-55K binding to the PML-NB component Sp100A apparently has an essential role in regulating adenovirus-mediated transformation processes. Specifically, when this E1B-55K/Sp100A complex recruits p53, Sp100A-induced activation of p53 transcriptional activity is effectively abolished.

The MANDELA study: A multicenter, randomized, open-label, parallel group trial to refine the use of everolimus after heart transplantation.

In recent years a series of trials has sought to define the optimal protocol for everolimus-based immunosuppression in heart transplantation, with the goal of minimizing exposure to calcineurin inhibitors (CNIs) and harnessing the non-immunosuppressive benefits of everolimus. Randomized studies have demonstrated that immunosuppressive potency can be maintained in heart transplant patients receiving everolimus despite marked CNI reduction, although very early CNI withdrawal may be inadvisable. A potential renal advantage has been shown for everolimus, but the optimal time for conversion and the adequate reduction in CNI exposure remain to be defined.

Viral Mimicry to Usurp Ubiquitin and SUMO Host Pathways.

Posttranslational modifications (PTMs) of proteins include enzymatic changes by covalent addition of cellular regulatory determinants such as ubiquitin (Ub) and small ubiquitin-like modifier (SUMO) moieties. These modifications are widely used by eukaryotic cells to control the functional repertoire of proteins. Over the last decade, it became apparent that the repertoire of ubiquitiylation and SUMOylation regulating various biological functions is not restricted to eukaryotic cells, but is also a feature of human virus families, used to extensively exploit complex host-cell networks and homeostasis.

Impact of switching from mycophenolate mofetil to enteric-coated mycophenolate sodium on gastrointestinal side effects in patients with autoimmune disease: a Phase III, open-label, single-arm, multicenter study.

Background: The purpose of this study was to assess changes in gastrointestinal symptom severity in patients with autoimmune disease who were switched from mycophenolate mofetil to enteric-coated mycophenolate sodium (EC-MPS).

Methods: In this national, explorative, single-arm study, 111 patients were enrolled and switched to equimolar EC-MPS at baseline. The primary endpoint was change in the Gastrointestinal Symptom Rating Scale (GSRS) total score after 6-8 weeks of treatment (Visit 2).

Fast calculating surrogate models for leg and head impact in vehicle-pedestrian collision simulations.

Objective: In previous research, a tool chain to simulate vehicle-pedestrian accidents from ordinary driving state to in-crash has been developed. This tool chain allows for injury criteria-based, vehicle-specific (geometry, stiffness, active safety systems, etc.) assessments.

Evaluating the efficacy, safety and evolution of renal function with early initiation of everolimus-facilitated tacrolimus reduction in de novo liver transplant recipients: Study protocol for a randomized controlled trial.

Background: Introduction of calcineurin inhibitors had led to improved survival rates in liver transplant recipients. However, long-term use of calcineurin inhibitors is associated with a higher risk of chronic renal failure, neurotoxicity, de novo malignancies, recurrence of hepatitis C viral (HCV) infection and hepatocellular carcinoma. Several studies have shown that everolimus has the potential to provide protection against viral replication, malignancy, and progression of fibrosis, as well as preventing nephrotoxicity by facilitating calcineurin inhibitor reduction without compromising efficacy.

Secreted frizzled-related protein 4 predicts progression of autosomal dominant polycystic kidney disease.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a common autosomal dominant condition associated with renal cysts and development of renal failure. With the availability of potential therapies, one major obstacle remains the lack of readily available parameters that identify patients at risk for disease progression and/or determine the efficacy of therapeutic interventions within short observation periods. Increased total kidney volume (TKV) correlates with disease progression, but it remains unknown how accurate this parameter can predict disease progression at early stages.

PML isoforms IV and V contribute to adenovirus-mediated oncogenic transformation by functionally inhibiting the tumor-suppressor p53.

Although modulation of the cellular tumor-suppressor p53 is considered to have the major role in E1A/E1B-55K-mediated tumorigenesis, other promyelocytic leukemia nuclear body (PML-NB)/PML oncogenic domain (POD)-associated factors including SUMO, Mre11, Daxx, as well as the integrity of these nuclear bodies contribute to the transformation process. However, the biochemical consequences and oncogenic alterations of PML-associated E1B-55K by SUMO-dependent PML-IV and PML-V interaction have so far remained elusive. We performed mutational analysis to define a PML interaction motif within the E1B-55K polypeptide.

Sp100 isoform-specific regulation of human adenovirus 5 gene expression.

Unlabelled: Promyelocytic leukemia nuclear bodies (PML-NBs) are nuclear structures that accumulate intrinsic host factors to restrict viral infections. To ensure viral replication, these must be limited by expression of viral early regulatory proteins that functionally inhibit PML-NB-associated antiviral effects. To benefit from the activating capabilities of Sp100A and simultaneously limit repression by Sp100B, -C, and -HMG, adenoviruses (Ads) employ several features to selectively and individually target these isoforms.

High-affinity Rb binding, p53 inhibition, subcellular localization, and transformation by wild-type or tumor-derived shortened Merkel cell polyomavirus large T antigens.

Unlabelled: Interference with tumor suppressor pathways by polyomavirus-encoded tumor antigens (T-Ags) can result in transformation. Consequently, it is thought that T-Ags encoded by Merkel cell polyomavirus (MCPyV), a virus integrated in ∼90% of all Merkel cell carcinoma (MCC) cases, are major contributors to tumorigenesis. The MCPyV large T-Ag (LT-Ag) has preserved the key functional domains present in all family members but has also acquired unique regions that flank the LxCxE motif.

SPOC1-mediated antiviral host cell response is antagonized early in human adenovirus type 5 infection.

Little is known about immediate phases after viral infection and how an incoming viral genome complex counteracts host cell defenses, before the start of viral gene expression. Adenovirus (Ad) serves as an ideal model, since entry and onset of gene expression are rapid and highly efficient, and mechanisms used 24-48 hours post infection to counteract host antiviral and DNA repair factors (e.g.

Role of E1B55K in E4orf6/E1B55K E3 ligase complexes formed by different human adenovirus serotypes.

The E4orf6 protein of serotypes representing all human adenovirus species forms Cullin-based E3 ubiquitin ligase complexes that facilitate virus infection by inducing degradation of cellular proteins that impede efficient viral replication. This complex also includes the viral E1B55K product believed to bind and introduce substrates for ubiquitination. Heterogeneity in the composition of these ligases exists, as some serotypes form Cul5-based complexes whereas others utilize Cul2.

Aggresome formation by the adenoviral protein E1B55K is not conserved among adenovirus species and is not required for efficient degradation of nuclear substrates.

Much of the work on the basic molecular biology of human adenoviruses has been carried out on a very limited number of the more than 60 serotypes, primarily the highly related species C viruses adenovirus type 5 (Ad5) and Ad2 and, to some extent, Ad12 of species A. Until recently, it has been widely assumed that insights obtained with these model viruses were representative of all human adenoviruses. Recent studies on the E3 ubiquitin ligase formed by the viral E1B55K and E4orf6 proteins with a cellular Cullin-based complex indicated that although all species form such a functional complex, significant variations exist in terms of complex composition and the substrates that are degraded.

Control of human adenovirus type 5 gene expression by cellular Daxx/ATRX chromatin-associated complexes.

Death domain-associated protein (Daxx) cooperates with X-linked α-thalassaemia retardation syndrome protein (ATRX), a putative member of the sucrose non-fermentable 2 family of ATP-dependent chromatin-remodelling proteins, acting as the core ATPase subunit in this complex, whereas Daxx is the targeting factor, leading to histone deacetylase recruitment, H3.3 deposition and transcriptional repression of cellular promoters. Despite recent findings on the fundamental importance of chromatin modification in host-cell gene regulation, it remains unclear whether adenovirus type 5 (Ad5) transcription is regulated by cellular chromatin remodelling to allow efficient virus gene expression.

The adenoviral oncogene E1A-13S interacts with a specific isoform of the tumor suppressor PML to enhance viral transcription.

PML nuclear bodies (PML NBs), also called ND10, are matrix-bound nuclear structures that have been implicated in a variety of functions, including DNA repair, transcriptional regulation, protein degradation, and tumor suppression. These domains are also known for their potential to mediate an intracellular defense mechanism against many virus types. This is likely why they are targeted and subsequently manipulated by numerous viral proteins.

Cross-talk between phosphorylation and SUMOylation regulates transforming activities of an adenoviral oncoprotein.

Since the discovery of post-translational modification (PTM) by the small ubiquitin-related modifiers (SUMOs), a multitude of proteins have been described to be reversibly modified, resulting in the alteration of several cellular pathways. Interestingly, various pathogens gain access to this modification system, although the molecular mechanisms and functional consequences are barely understood. We show here that the adenoviral oncoprotein E1B-55K is a substrate of the SUMO conjugation system, which is directly linked to its C-terminal phosphorylation.

Transcriptional activation of the adenoviral genome is mediated by capsid protein VI.

Gene expression of DNA viruses requires nuclear import of the viral genome. Human Adenoviruses (Ads), like most DNA viruses, encode factors within early transcription units promoting their own gene expression and counteracting cellular antiviral defense mechanisms. The cellular transcriptional repressor Daxx prevents viral gene expression through the assembly of repressive chromatin remodeling complexes targeting incoming viral genomes.

Adenovirus degradation of cellular proteins.

Eukaryotic cells orchestrate constant synthesis and degradation of intracellular components, including soluble proteins and organelles. The two major intracellular degradation pathways are the ubiquitin/proteasome system and autophagy. Whereas ubiquitin/proteasome system is involved in rapid degradation of proteins, autophagy selectively removes protein aggregates and damaged organelles.