TRIM27 Negatively Regulates NOD2 by Ubiquitination and Proteasomal Degradation

NOD2, the nucleotide-binding domain and leucine-rich repeat containing gene family (NLR) member 2 is involved in mediating antimicrobial responses. Dysfunctional NOD2 activity can lead to severe inflammatory disorders, but the regulation of NOD2 is still poorly understood. Recently, proteins of the tripartite motif (TRIM) protein family have emerged as regulators of innate immune responses by acting as E3 ubiquitin ligases. We identified TRIM27 as a new specific binding partner for NOD2. We show that NOD2 physically interacts with TRIM27 via the nucleotide-binding domain, and that NOD2 activation enhances this interaction. Dependent on functional TRIM27, ectopically expressed NOD2 is ubiquitinated with K48-linked ubiquitin chains followed by proteasomal degradation. Accordingly, TRIM27 affects NOD2-mediated pro-inflammatory responses. NOD2 mutations are linked to susceptibility to Crohns disease. We found that TRIM27 expression is increased in Crohns disease patients, underscoring a physiological role of TRIM27 in regulating NOD2 signaling. In HeLa cells, TRIM27 is partially localized in the nucleus. We revealed that ectopically expressed NOD2 can shuttle to the nucleus in a Walker A dependent manner, suggesting that NOD2 and TRIM27 might functionally cooperate in the nucleus. We conclude that TRIM27 negatively regulates NOD2-mediated signaling by degradation of NOD2 and suggest that TRIM27 could be a new target for therapeutic intervention in NOD2-associated diseases.Funding Agencies|German Research Foundation (DFG)|SFB670-NG01|Swedish Society of Medicine||Regional Research Council of South-East Sweden (FORSS)||Swedish Research Council division of Medicine||Gustav V 90th anniversary foundation||Italian Telethon Foundation||DFG|SE 1122/2-1|</p

The Rotterdam Study: 2012 objectives and design update

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods

Post-mortem assessment in vascular dementia: advances and aspirations.

BACKGROUND: Cerebrovascular lesions are a frequent finding in the elderly population. However, the impact of these lesions on cognitive performance, the prevalence of vascular dementia, and the pathophysiology behind characteristic in vivo imaging findings are subject to controversy. Moreover, there are no standardised criteria for the neuropathological assessment of cerebrovascular disease or its related lesions in human post-mortem brains, and conventional histological techniques may indeed be insufficient to fully reflect the consequences of cerebrovascular disease. DISCUSSION: Here, we review and discuss both the neuropathological and in vivo imaging characteristics of cerebrovascular disease, prevalence rates of vascular dementia, and clinico-pathological correlations. We also discuss the frequent comorbidity of cerebrovascular pathology and Alzheimer's disease pathology, as well as the difficult and controversial issue of clinically differentiating between Alzheimer's disease, vascular dementia and mixed Alzheimer's disease/vascular dementia. Finally, we consider additional novel approaches to complement and enhance current post-mortem assessment of cerebral human tissue. CONCLUSION: Elucidation of the pathophysiology of cerebrovascular disease, clarification of characteristic findings of in vivo imaging and knowledge about the impact of combined pathologies are needed to improve the diagnostic accuracy of clinical diagnoses

Molecular Targeted Positron Emission Tomography Imaging and Radionuclide Therapy of Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) has an inauspicious prognosis, mainly due to difficulty in early detection of the disease by the current imaging modalities. The upcoming development of tumour-specific tracers provides an alternative solution for more accurate diagnostic imaging techniques for staging and therapy response monitoring. The future goal to strive for, in a patient with PDAC, should definitely be first to receive a diagnostic dose of an antibody labelled with a radionuclide and to subsequently receive a therapeutic dose of the same labelled antibody with curative intent. In the first part of this paper, we summarise the available evidence on tumour-targeted diagnostic tracers for molecular positron emission tomography (PET) imaging that have been tested in humans, together with their clinical indications. Tracers such as radiolabelled prostate-specific membrane antigen (PSMA)&mdash;in particular, 18F-labelled PSMA&mdash;already validated and successfully implemented in clinical practice for prostate cancer, also seem promising for PDAC. In the second part, we discuss the theranostic applications of these tumour-specific tracers. Although targeted radionuclide therapy is still in its infancy, lessons can already be learned from early publications focusing on dose fractioning and adding a radiosensitiser, such as gemcitabine

Seeking new strength at coffeeshops

Background: The Selvester QRS score (S-score) estimates myocardial scar using electrocardio-graphic criteria. We evaluated the S-score for left bundle branch block (LBBB).Material and methods: Studied were 36 patients who developed persistent LBBB upon transcatheter aortic valve implantation (TAVI, TAVI-LBBB group) and 36 matched patients with persistent narrow QRS (TAVI-nQRS group). Electrocardiograms were recorded before and briefly after TAVI and during similar to 6 months follow-up. S-score was calculated using criteria for hypertrophic (in absence of LBBB) or LBBB hearts.Results: In TAVI-LBBB patients correlation between S-scores pre-TAVI and post-TAVI was absent (R-2 = 0.023). High S-scores post-TAVI occurred in patients with low pre-TAVI scores. Pre-post TAVI scores correlated weakly in TAVI-nQRS (R-2 = 0.182), indicating a possible influence of ventricular unloading by TAVI. In both groups S-scores at post-TAVI and follow-up compared reasonably (R-2 = 0.389 and R-2 = 0.386), indicating reproducibility in more stable conditions.Conclusion: This study indicates that the use of the LBBB S-score criteria overestimates scar size and that caution is recommended in the use of the score in patients with LBBB. (C) 2017 The Author(s). Published by Elsevier Inc.</p

Transcatheter Aortic Valve Implantation-Induced Left Bundle Branch Block: Causes and Consequences

Transcatheter aortic valve implantation (TAVI) is an alternative treatment option for patients with severe aortic valve stenosis who do not qualify for surgical aortic valve replacement (AVR). Besides its proven clinical benefits, one of the complications of TAVI is the creation of conduction abnormalities, like left bundle branch block (LBBB). New LBBB occurs between 7 and 65 % of cases, numbers that differ considerably between devices. In this review, we discuss the possible causes and the clinical significance of TAVI-induced LBBB. Several device- and procedural-related factors seem responsible for the development of LBBB, of which depth of implantation and balloon-annulus diameter ratio are the most important ones. TAVI-induced LBBB negatively affects cardiac function and hospitalization, but its impact on mortality is subject of debate. Future research and registries should implement strict diagnostic criteria for LBBB together with recording of its timing and persistence