Recurrence risk of occult micrometastases and isolated tumor cells in early stage endometrial cancer: A case control study

Objectives: To determine whether previously undetected occult micrometastasis (MM) or isolated tumor cells (ITC) is associated with increased recurrence odds in stage I-II endometrioid adenocarcinoma. Methods: Women with recurrent stage I/II EC who had complete pelvic and para-aortic were identified as the outcome of interest. A case-control study was designed with the exposure defined as occult MM/ITC not seen on original nodal pathology. Controls were found by frequency-matching in a 1:2 case control ratio. Original nodal slides were re-reviewed, stained and tested with immunohistochemical to detect occult MM/ITC and the odds of associated recurrence was calculated. Results: Of 153 included, 50 with and 103 without recurrence, there was no difference in age (p = 0.46), race (p = 0.24), stage (p = 0.75), FIGO grade (p = 0.64), lymphovascular space invasion (LVSI); p = 1.00, or GOG 99 high-intermediate risk (HIR) criteria (p = 0.35). A total of 18 ITC (11.8%) and 3 MM (2.0%) not previously identified were found in 19 patients. Finding occult MM/ITC was not associated with more lymph nodes (LN) removed (p = 0.67) or tumor grade (p = 0.48) but was significantly associated with stage (p \u3c 0.01). LVSI (p = 0.09) and meeting high-intermediate risk criteria (p = 0.09), were closely associated but not statistically significant. Isolated ITC were not associated with increased odds for recurrence (OR 0.71, CL: 0.20 - 2.22, p = 0.57), recurrence free survival (RFS) (p = 0.85) or overall survival (OS) (p = 0.92). Conclusions: In early-stage EC, identification of occult MM or ITC is uncommon and associated with stage. The presence of ITC was not associated with increased odds of recurrence. Adjusting stage or treatment may avoided based on ITC alone. Isolated MM were rare in our population, and further investigation is warranted

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Regulation of USP37 Expression by REST-associated G9a-dependent Histone Methylation

The deubiquitylase (DUB) USP37 is a component of the ubiquitin system and controls cell proliferation by regulating the stability of the cyclin-dependent kinase inhibitor 1B, (CDKN1B/p27Kip1). The expression of USP37 is down-regulated in human medulloblastoma tumor specimens. In the current study we show that USP37 prevents medulloblastoma growth in mouse orthotopic models, suggesting that it has tumor suppressive properties in this neural cancer. Here, we also report on the mechanism underlying USP37 loss in medulloblastoma. Previously, we observed that the expression of USP37 is transcriptionally repressed by the RE1 Silencing Transcription Factor (REST), which requires chromatin remodeling factors for its activity. Genetic and pharmacological approaches were employed to identify a specific role for G9a, a histone methyltransferase (HMT), in promoting methylation of histone H3 lysine-9 (H3K9) mono- and di-methylation, and surprisingly tri-methylation, at the USP37 promoter to repress its gene expression. G9a inhibition also blocked the tumorigenic potential of medulloblastoma cells in vivo. Using isogenic low- and high-REST medulloblastoma cells, we further showed a REST-dependent elevation in G9a activity, which further increased mono- and tri-methylation of histone H3K9, accompanied by down regulation of USP37 expression. Together, these findings reveal a role for REST-associated G9a and histone H3K9 methylation in the repression of USP37 expression in medulloblastoma

Differential central pathology and cognitive impairment in pre-diabetic and diabetic mice

Although age remains the main risk factor to suffer Alzheimer's disease (AD) and vascular dementia (VD), type 2 diabetes (T2D) has turned up as a relevant risk factor for dementia. However, the ultimate underlying mechanisms for this association remain unclear. In the present study we analyzed central nervous system (CNS) morphological and functional consequences of long-term insulin resistance and T2D in db/db mice (leptin receptor KO mice). We also included C57Bl6 mice fed with high fat diet (HFD) and a third group of C57Bl6 streptozotocin (STZ) treated mice. Db/db mice exhibited pathological characteristics that mimic both AD and VD, including age dependent cognitive deterioration, brain atrophy, increased spontaneous hemorrhages and tau phosphorylation, affecting the cortex preferentially. A similar profile was observed in STZ-induced diabetic mice. Moreover metabolic parameters, such as body weight, glucose and insulin levels are good predictors of many of these alterations in db/db mice. In addition, in HFD-induced hyperinsulinemia in C57Bl6 mice, we only observed mild CNS alterations, suggesting that central nervous system dysfunction is associated with well established T2D. Altogether our results suggest that T2D may promote many of the pathological and behavioral alterations observed in dementia, supporting that interventions devoted to control glucose homeostasis could improve dementia progress and prognosis.M.G.-A. was supported by Ramon y Cajal program RYC-2008-02333, ISCIII – Ministerio de Economía y Competitividad, Spain. Junta de Andalucia, Proyectos de Investigación de Excelencia (P11-CTS-7847), Instituto de Salud Carlos III and FEDER (European Union), cofinanced by Fondo Europeo de Desarrollo Regional “Una manera de hacer Europa” PI12/00675 (Monica Garcia-Alloza). I.C.-C. was supported by RYC-2011-08101, ISCIII-Subdirección General de Evaluación y Fomento de la Investigación, Spain (PS09/00671), Europe-FP7 Marie Curie Grant (IRG-247835).Peer reviewe

Experimental seismic assessment and protection of museum artefacts

Earthquakes are a major threat to monuments and to museums and their valuable contents worldwide. The protection of cultural heritage structures and also of museums and their treasures against earthquakes is hence a top priority. The paper will present large scale shaking table tests on cultural heritage assets and will emphasize on the use computing models in tandem with experimental testing. More specifically, the paper will present an extensive experimental campaign on the seismic response of artefacts, with emphasis on statues and busts. The tests have been carried out in the framework of SEREME project (Seismic Resilience of Museum Contents) at the AZALEE seismic simulator of CEA in Saclay, Paris under the auspices of the EC funded SERA project. The aim is to understand the seismic response of statues and busts and then develop novel and cost-effective risk mitigation schemes for improving the seismic resilience of museum valuable contents. The study is focused on the investigation of the seismic response of two real-scale marble roman statues and three busts of three roman emperors standing on pedestals of different types and size. Both non-isolated and seismically isolated artefacts are considered, while two new and highly efficient base isolation systems, tailored to art objects, have been tested. The first isolator is a pendulum-based system, while the second utilizes Shape Memory Alloy wires. Specifically tailored, numerical models of varying complexity, for single and two-block rocking systems, were developed for the needs of this study and are also assessed against the experimental result