Genetic analyses of undifferentiated small round cell sarcoma identifies a novel sarcoma subtype with a recurrent CRTC1-SS18 gene fusion

In recent years, undifferentiated small round cell sarcomas (USRCSs) have been divided into a variety of new, rare, sarcoma subtypes, including the group of Ewing-like sarcomas, which have the morphological appearance of Ewing sarcomas, but carry CIC-DUX4, BCOR-CCNB3 and other gene fusions different from the classic EWSR1-ETS gene fusion. Using high-throughput RNA-sequencing (RNA-seq) analyses, we identified a novel recurrent gene fusion, CRTC1-SS18, in two cases of USRCS that lacked any known translocation. RNA-seq results were confirmed by reverse transcription polymerase chain reaction, long-range polymerase chain reaction, and fluorescence in situ hybridization. In vitro, we showed that the cells expressing the gene fusion were morphologically distinct and had enhanced oncogenic potential as compared with control cells. Expression profile comparisons with tumours of other sarcoma subtypes demonstrated that both cases clustered close to EWSR1-CREB1-positive tumours. Moreover, these analyses indicated enhanced NTRK1 expression in CRTC1-SS18-positive tumours. We conclude that the novel gene fusion identified in this study adds a new subtype to the USRCSs with unique gene signatures, and may be of therapeutic relevance. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

Cervical cancer screening: target age bracket, screening frequency and screening method: review of recent evidence and comparison with the Portuguese performance indicator

Esta revisão teve por objetivo avaliar a força de evidência do indicador de desempenho português relativo ao rastreio do Câncer do Colo do Útero (CCU): (1) limites etários das mulheres da população geral que o devem realizar, a (2) periodicidade com que deve ser realizado e (3) qual o melhor exame de rastreio. Foram pesquisados os seguintes termos MeSH: vaginal smears, age groups, periodicity, methods, uterine cervical cancer. Foram excluídos os artigos que não abordavam o objetivo da investigação ou que não fossem redigidos em Inglês, Português ou Espanhol. Para interpretar os artigos selecionados foi utilizada a classificação SORT. Foram encontrados 197 artigos, dos quais seleccionados 9: 1 revisão sistemática (RS), 1 estudo clínico controlado aleatorizado, 2 estudos observacionais retrospectivos e 5 normas de orientação clínica (NOC). Os autores optaram por incluir nesta revisão mais 4 NOCs e 2 RSs por considerarem ser relevantes para a população Portuguesa, apesar de não resultarem da pesquisa efectuada. Os estudos sugerem realização do rastreio entre os 21 e 25 até aos 65 anos, com uma periodicidade trienal usando a citologia convencional. Existe ainda controvérsia no que toca aos 3 objetivos deste artigo (limites etários, frequência e método).The scope of this review was to assess the strength of evidence of Portuguese performance indicators on Cervical Cancer screening: (1) age group of the women that should be screened for cervical cancer; (2) frequency of screening; and (3) the best method for screening. The following MeSH terms were searched: vaginal smears, age groups, periodicity, methods, uterine cervical cancer. Articles not reflecting the study objectives or not available in English, Portuguese or Spanish were excluded. The SORT classification was used to rate the articles selected.Of the 197 articles found, 9 that met all study criteria were selected for inclusion in this review. These included 1 systematic review, 1 randomized controlled clinical trial, 2 retrospective studies and 5 clinical guidelines. The authors also chose to include 4 clinical guidelines and two systematic reviews relevant to the Portuguese population even though they did not appear in the initial search of the literature. The studies suggest screening women between the ages of 21 to 25 years and 65 years of age, once every three years using conventional cytology. There is still controversy regarding the three objectives of this study (target age bracket, screening frequency and screening method)

Deformation of Codimension-2 Surface and Horizon Thermodynamics

The deformation equation of a spacelike submanifold with an arbitrary codimension is given by a general construction without using local frames. In the case of codimension-1, this equation reduces to the evolution equation of the extrinsic curvature of a spacelike hypersurface. In the more interesting case of codimension-2, after selecting a local null frame, this deformation equation reduces to the well known (cross) focusing equations. We show how the thermodynamics of trapping horizons is related to these deformation equations in two different formalisms: with and without introducing quasilocal energy. In the formalism with the quasilocal energy, the Hawking mass in four dimension is generalized to higher dimension, and it is found that the deformation of this energy inside a marginal surface can be also decomposed into the contributions from matter fields and gravitational radiation as in the four dimension. In the formalism without the quasilocal energy, we generalize the definition of slowly evolving future outer trapping horizons proposed by Booth to past trapping horizons. The dynamics of the trapping horizons in FLRW universe is given as an example. Especially, the slowly evolving past trapping horizon in the FLRW universe has close relation to the scenario of slow-roll inflation. Up to the second order of the slowly evolving parameter in this generalization, the temperature (surface gravity) associated with the slowly evolving trapping horizon in the FLRW universe is essentially the same as the one defined by using the quasilocal energy.Comment: Latex, 61 pages, no figures; v2, type errors corrected; v3, references and comments are added, English is improved, to appear in JHE

Mental Health of Parents and Life Satisfaction of Children: A Within-Family Analysis of Intergenerational Transmission of Well-Being

This paper addresses the extent to which there is an intergenerational transmission of mental health and subjective well-being within families. Specifically it asks whether parents’ own mental distress influences their child’s life satisfaction, and vice versa. Whilst the evidence on daily contagion of stress and strain between members of the same family is substantial, the evidence on the transmission between parental distress and children’s well-being over a longer period of time is sparse. We tested this idea by examining the within-family transmission of mental distress from parent to child’s life satisfaction, and vice versa, using rich longitudinal data on 1,175 British youths. Results show that parental distress at year t-1 is an important determinant of child’s life satisfaction in the current year. This is true for boys and girls, although boys do not appear to be affected by maternal distress levels. The results also indicated that the child’s own life satisfaction is related with their father’s distress levels in the following year, regardless of the gender of the child. Finally, we examined whether the underlying transmission correlation is due to shared social environment, empathic reactions, or transmission via parent-child interaction

Allelic imbalance in gene expression as a guide to cis-acting regulatory single nucleotide polymorphisms in cancer cells

Using the relative expression levels of two SNP alleles of a gene in the same sample is an effective approach for identifying cis-acting regulatory SNPs (rSNPs). In the current study, we established a process for systematic screening for cis-acting rSNPs using experimental detection of AI as an initial approach. We selected 160 expressed candidate genes that are involved in cancer and anticancer drug resistance for analysis of AI in a panel of cell lines that represent different types of cancers and have been well characterized for their response patterns against anticancer drugs. Of these genes, 60 contained heterozygous SNPs in their coding regions, and 41 of the genes displayed imbalanced expression of the two cSNP alleles. Genes that displayed AI were subjected to bioinformatics-assisted identification of rSNPs that alter the strength of transcription factor binding. rSNPs in 15 genes were subjected to electrophoretic mobility shift assay, and in eight of these genes (APC, BCL2, CCND2, MLH1, PARP1, SLIT2, YES1, XRCC1) we identified differential protein binding from a nuclear extract between the SNP alleles. The screening process allowed us to zoom in from 160 candidate genes to eight genes that may contain functional rSNPs in their promoter regions

Notch signaling in mouse blastocyst development and hatching

Research Areas: Developmental BiologyBackground: Mammalian early embryo development requires a well-orchestrated interplay of cell signaling pathways. Notch is a major regulatory pathway involved in cell-fate determination in embryonic and adult scenarios. However, the role of Notch in embryonic pre-implantation development is controversial. In particular, Notch role on blastocyst development and hatching remains elusive, and a complete picture of the transcription and expression patterns of Notch components during this time-period is not available. Results: This study provided a comprehensive view on the dynamics of individual embryo gene transcription and protein expression patterns of Notch components (receptors Notch1–4; ligands Dll1 and Dll4, Jagged1–2; and effectors Hes1–2), and their relationship with transcription of gene markers of pluripotency and differentiation (Sox2, Oct4, Klf4, Cdx2) during mouse blastocyst development and hatching. Transcription of Notch1–2, Jagged1–2 and Hes1 was highly prevalent and dynamic along stages of development, whereas transcription of Notch3–4, Dll4 and Hes2 had a low prevalence among embryos. Transcription levels of Notch1, Notch2, Jagged2 and Hes1 correlated with each other and with those of pluripotency and differentiation genes. Gene transcription was associated to protein expression, except for Jagged2, where high transcription levels in all embryos were not translated into protein. Presence of Notch signaling activity was confirmed through nuclear NICD and Hes1 detection, and downregulation of Hes1 transcription following canonical signaling blockade with DAPT. In vitro embryo culture supplementation with Jagged1 had no effect on embryo developmental kinetics. In contrast, supplementation with Jagged2 abolished Jagged1 transcription, downregulated Cdx2 transcription and inhibited blastocyst hatching. Notch signaling blockade by DAPT downregulated transcription of Sox2, and retarded embryo hatching. Conclusion: Transcription of Notch genes showed a dynamic pattern along blastocyst development and hatching. Data confirmed Notch signaling activity, and lead to the suggestion that Notch canonical signaling may be operating through Notch1, Notch3, Jagged1 and Hes1. Embryo culture supplementation with Jagged1 and Jagged2 unveiled a possible regulatory effect between Jagged1, Cdx2 and blastocyst hatching. Overall, results indicate that a deregulation in Notch signaling, either by its over or under-activation, affects blastocyst development and hatching.info:eu-repo/semantics/publishedVersio

Nonequilibrium Steady States of Matrix Product Form: A Solver's Guide

We consider the general problem of determining the steady state of stochastic nonequilibrium systems such as those that have been used to model (among other things) biological transport and traffic flow. We begin with a broad overview of this class of driven diffusive systems - which includes exclusion processes - focusing on interesting physical properties, such as shocks and phase transitions. We then turn our attention specifically to those models for which the exact distribution of microstates in the steady state can be expressed in a matrix product form. In addition to a gentle introduction to this matrix product approach, how it works and how it relates to similar constructions that arise in other physical contexts, we present a unified, pedagogical account of the various means by which the statistical mechanical calculations of macroscopic physical quantities are actually performed. We also review a number of more advanced topics, including nonequilibrium free energy functionals, the classification of exclusion processes involving multiple particle species, existence proofs of a matrix product state for a given model and more complicated variants of the matrix product state that allow various types of parallel dynamics to be handled. We conclude with a brief discussion of open problems for future research.Comment: 127 pages, 31 figures, invited topical review for J. Phys. A (uses IOP class file

Reduced Rate of Neural Differentiation in the Dentate Gyrus of Adult Dysbindin Null (Sandy) Mouse

Genetic variations in the gene encoding dysbindin has consistently been associated with schizophrenia and bipolar disorder, although little is known about the neural functions carried out by dysbindin. To gain some insight into this area, we took advantage of the readily available dysbindin-null mouse sandy (sdy−/−) and studied hippocampal neurogenesis using thymidine analogue bromodeoxuridine (BrdU). No significant differences were found in the proliferation (4 hours) or survival (1, 4 and 8 weeks after the last BrdU injection) of progenitors in the subgranular regions of the dentate gyrus between sdy−/− and sdy+/+ (control) mice. However, 4 weeks after the last BrdU injection, a significant reduction was observed in the ratio of neuronal differentiation in sdy−/− when compared to that of sdy+/+ (sdy+/+  = 87.0±5.3% vs. sdy−/−  = 71.3±8.3%, p = 0.01). These findings suggest that dysbindin plays a role during differentiation process in the adult hippocampal neurogenesis and that its deficit may negatively affect neurogenesis-related functions such as cognition and mood

ANGPTL4 variants E40K and T266M are associated with lower fasting triglyceride levels in Non-Hispanic White Americans from the Look AHEAD Clinical Trial

<p>Abstract</p> <p>Background</p> <p>Elevated triglyceride levels are a risk factor for cardiovascular disease. Angiopoietin-like protein 4 (Angptl4) is a metabolic factor that raises plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). In non-diabetic individuals, the <it>ANGPTL4 </it>coding variant E40K has been associated with lower plasma triglyceride levels while the T266M variant has been associated with more modest effects on triglyceride metabolism. The objective of this study was to determine whether ANGPTL4 E40K and T266M are associated with triglyceride levels in the setting of obesity and T2D, and whether modification of triglyceride levels by these genetic variants is altered by a lifestyle intervention designed to treat T2D.</p> <p>Methods</p> <p>The association of <it>ANGPTL4 </it>E40K and T266M with fasting triglyceride levels was investigated in 2,601 participants from the Look AHEAD Clinical Trial, all of whom had T2D and were at least overweight. Further, we tested for an interaction between genotype and treatment effects on triglyceride levels.</p> <p>Results</p> <p>Among non-Hispanic White Look AHEAD participants, <it>ANGPTL4 </it>K40 carriers had mean triglyceride levels of 1.61 ± 0.62 mmol/L, 0.33 mmol/L lower than E40 homozygotes (p = 0.001). Individuals homozygous for the minor M266 allele (MAF 30%) had triglyceride levels of 1.75 ± 0.58 mmol/L, 0.24 mmol/L lower than T266 homozygotes (p = 0.002). The association of the M266 with triglycerides remained significant even after removing K40 carriers from the analysis (p = 0.002). There was no interaction between the weight loss intervention and genotype on triglyceride levels.</p> <p>Conclusions</p> <p>This is the first study to demonstrate that the <it>ANGPTL4 </it>E40K and T266M variants are associated with lower triglyceride levels in the setting of T2D. In addition, our findings demonstrate that <it>ANGPTL4 </it>genotype status does not alter triglyceride response to a lifestyle intervention in the Look AHEAD study.</p