Beta cell function in type 1 diabetes determined from clinical and fasting biochemical variables

AIMS/HYPOTHESIS: Beta cell function in type 1 diabetes is commonly assessed as the average plasma C-peptide concentration over 2 h following a mixed-meal test (CPAVE). Monitoring of disease progression and response to disease-modifying therapy would benefit from a simpler, more convenient and less costly measure. Therefore, we determined whether CPAVE could be reliably estimated from routine clinical variables. METHODS: Clinical and fasting biochemical data from eight randomised therapy trials involving participants with recently diagnosed type 1 diabetes were used to develop and validate linear models to estimate CPAVE and to test their accuracy in estimating loss of beta cell function and response to immune therapy. RESULTS: A model based on disease duration, BMI, insulin dose, HbA1c, fasting plasma C-peptide and fasting plasma glucose most accurately estimated loss of beta cell function (area under the receiver operating characteristic curve [AUROC] 0.89 [95% CI 0.87, 0.92]) and was superior to the commonly used insulin-dose-adjusted HbA1c (IDAA1c) measure (AUROC 0.72 [95% CI 0.68, 0.76]). Model-estimated CPAVE (CPEST) reliably identified treatment effects in randomised trials. CPEST, compared with CPAVE, required only a modest (up to 17%) increase in sample size for equivalent statistical power. CONCLUSIONS/INTERPRETATION: CPEST, approximated from six variables at a single time point, accurately identifies loss of beta cell function in type 1 diabetes and is comparable to CPAVE for identifying treatment effects. CPEST could serve as a convenient and economical measure of beta cell function in the clinic and as a primary outcome measure in trials of disease-modifying therapy in type 1 diabetes

Genome-wide analysis reveals no evidence of trans chromosomal regulation of mammalian immune development.

It has been proposed that interactions between mammalian chromosomes, or transchromosomal interactions (also known as kissing chromosomes), regulate gene expression and cell fate determination. Here we aimed to identify novel transchromosomal interactions in immune cells by high-resolution genome-wide chromosome conformation capture. Although we readily identified stable interactions in cis, and also between centromeres and telomeres on different chromosomes, surprisingly we identified no gene regulatory transchromosomal interactions in either mouse or human cells, including previously described interactions. We suggest that advances in the chromosome conformation capture technique and the unbiased nature of this approach allow more reliable capture of interactions between chromosomes than previous methods. Overall our findings suggest that stable transchromosomal interactions that regulate gene expression are not present in mammalian immune cells and that lineage identity is governed by cis, not trans chromosomal interactions

Program to improve the portion-size: design and application

[EUS] Ikerlan honen helburua, elikagaien anoen estimazioa hobetzeko programa baten diseinua eta programa honen aplikazioaren abantailak ebaluatzea izan zen. Emaitzek programaren inplementazioa arrakastatsua izan zela diote batetik eta datu bilketarako entrenamendu programa berrien garapenerako oinarriak eskaini ditzakeela diote bestetik.[ES] El objetivo de esta investigación es evaluar el diseño de un programa para mejorar la estimación de las provisiones de alimentos y las ventajas de su aplicación. Los resultados dicen, por una parte, que la implementación del programa ha sido un éxito y, por otra, que puede sentar las bases para el desarrollo de nuevos programas de entrenamiento para la recogida de datos.[FRE] L’objectif de ce travail de recherche est d’envisager l’élaboration d’un programme visant à améliorer l’estimation des provisions d’aliments et d’évaluer les avantages de son application. Les résultats montrent que, d’une part, l’application du programme a été un succès et, d’autre part, qu’il peut servir de base au développement d’autres programmes de simulation pour la collecte des données.Lan honek Eusko Ikaskuntzaren 2007. urteko ikerketa laguntza jaso du

Prediction of stature in adults: knee height measurements

[EUS] Lan honen helburua ohiko metodoen zein metodo ez-zuzenekoen bitartez (belaunerainoko altuera antropometroarekin eta zinta metrikoarekin) pertsona helduez osaturiko talde baten altuera zehaztea izan da. Ez-zuzeneko altuera zehaztapenek komunztadura altua erakutsi zuten benetako altuerarekin. Zinta metrikoaren bitartez neurturiko belaunerainoko altuerak komunztadura altuagoa erakutsi zuen benetako altuerarekin, antropometroaren bitartez definiturikoa baino.[ES] Este trabajo tiene como finalidad precisar la estatura de un grupo formado por personas adultas, mediante métodos tradicionales y métodos indirectos (altura de rodilla medida con el antropómetro y con cinta métrica). Las mediciones indirectas de la altura mostraron una gran concordancia con la estatura real. La altura de rodilla determinada mediante cinta métrica mostró una mayor concordancia con la estatura real que la estimada mediante antropómetro.[FRE] Ce travail vise à préciser la taille d'un groupe de personnes adultes, en utilisant des méthodes traditionnelles et des méthodes indirectes (hauteur du genou mesurée à l’aide de l’anthropomètre et d’un mètre). Les mesures indirectes ont montré une grande concordance avec la taille réelle. La hauteur du genou déterminée à l’aide du mètre a montré une plus forte corrélation avec la taille réelle telle que celle définie par l’anthropomètre.Lan honek Eusko Ikaskuntzaren 2009 urteko ikerketa laguntza jaso du

Degree of accuracy in estimating portions: influence of food form

[EUS] Ikerketa lan honen helburua entrenamendu programa baten ondoren elikagaien formek, anoak estimatzeko garaian duen eragina baloratzea da. Doitasun baxuenarekin estimaturiko elikagai amorfoak izan ziren, bai entrenamendu aurretik zein ondoren. Estimazioan eginiko akatsak txikitu egin ziren entrenamenduaren ondoren elikagai solido eta likidoetan, nahiz eta hilabete batzuk igaro ondoren akats hauek areagotu.[ES] El objeto de este trabajo de investigación es establecer, después de un programa de entrenamiento, la influencia que tiene la forma de los alimentos a la hora de calcular las raciones. Los alimentos que se estimaron con menor precisión fueron los amorfos tanto antes como después del entrenamiento. Los errores cometidos a la hora de la estimación se redujeron después del entrenamiento tanto en alimentos sólidos como en líquidos, aunque unos meses después esos errores aumentaron.[FRE] L’objectif de ce travail de recherche est d’établir l’influence, après la réalisation d’un programme d’entraînement, de la forme des aliments sur le calcul des rations. Les aliments qui ont été estimés avec une moindre précision sont été les amorphes, avant et après l’entraînement. Les erreurs d’estimation diminuent après l’entraînement, tant pour les aliments solides que liquides, bien que quelques mois plus tard ces erreurs augmentent.Lan honek eusko ikaskuntzaren 2008. urteko ikerketa laguntza jaso du

Long non-coding RNA dysregulation is a frequent event in non-small cell lung carcinoma pathogenesis

Background Long non-coding RNAs compose an important level of epigenetic regulation in normal physiology and disease. Despite the plethora of publications of lncRNAs in human cancer, the landscape is still unclear. Methods Microarray analysis in 44 NSCLC paired specimens was followed by qPCR-based validation in 29 (technical) and 38 (independent) tissue pairs. Cross-validation of the selected targets was achieved in 850 NSCLC tumours from TCGA datasets. Results Twelve targets were successfully validated by qPCR (upregulated: FEZF1-AS1, LINC01214, LINC00673, PCAT6, NUTM2A-AS1, LINC01929; downregulated: PCAT19, FENDRR, SVIL-AS1, LANCL1-AS1, ADAMTS9-AS2 and LINC00968). All of them were successfully cross-validated in the TCGA datasets. Abnormal DNA methylation was observed in the promoters of FENDRR, FEZF1-AS1, and SVIL-AS1. FEZF1-AS1 and LINC01929 were associated with survival in the TCGA set. Conclusions Our study provides through multiple levels of internal and external validation, a comprehensive list of dysregulated lncRNAs in NSCLC. We therefore envisage this dataset to serve as an important source for the lung cancer research community assisting future investigations on the involvement of lncRNAs in the pathogenesis of the disease and providing novel biomarkers for diagnosis, prognosis and therapeutic stratification

Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory

Metastasis arises from disseminated tumour cells (DTCs) that are characterized by intrinsic phenotypic plasticity and the capability of seeding to secondary organs. DTCs can remain latent for years before giving rise to symptomatic overt metastasis. In this context, DTCs fluctuate between a quiescent and proliferative state in response to systemic and microenvironmental signals including immune-mediated surveillance. Despite its relevance, how intrinsic mechanisms sustain DTCs plasticity has not been addressed. By interrogating the epigenetic state of metastatic cells, we find that tumour progression is coupled with the activation of oncogenic enhancers that are organized in variable interconnected chromatin domains. This spatial chromatin context leads to the activation of a robust transcriptional response upon repeated exposure to retinoic acid (RA). We show that this adaptive mechanism sustains the quiescence of DTCs through the activation of the master regulator SOX9. Finally, we determine that RA-stimulated transcriptional memory increases the fitness of metastatic cells by supporting the escape of quiescent DTCs from NK-mediated immune surveillance. Overall, these findings highlight the contribution of oncogenic enhancers in establishing transcriptional memories as an adaptive mechanism to reinforce cancer dormancy and immune escape, thus amenable for therapeutic intervention

DNA methylation epigenotypes in breast cancer molecular subtypes

12 páginas, 3 figuras, 3 tablas.-- et al.[Introduction]: Identification of gene expression-based breast cancer subtypes is considered a critical means of prognostication. Genetic mutations along with epigenetic alterations contribute to gene-expression changes occurring in breast cancer. So far, these epigenetic contributions to sporadic breast cancer subtypes have not been well characterized, and only a limited understanding exists of the epigenetic mechanisms affected in those particular breast cancer subtypes. The present study was undertaken to dissect the breast cancer methylome and to deliver specific epigenotypes associated with particular breast cancer subtypes. [Methods]: By using a microarray approach, we analyzed DNA methylation in regulatory regions of 806 cancer-related genes in 28 breast cancer paired samples. We subsequently performed substantial technical and biologic validation by pyrosequencing, investigating the top qualifying 19 CpG regions in independent cohorts encompassing 47 basal-like, 44 ERBB2+ overexpressing, 48 luminal A, and 48 luminal B paired breast cancer/adjacent tissues. With the all-subset selection method, we identified the most subtype-predictive methylation profiles in multivariable logistic regression analysis. [Results]: The approach efficiently recognized 15 individual CpG loci differentially methylated in breast cancer tumor subtypes. We further identified novel subtype-specific epigenotypes that clearly demonstrate the differences in the methylation profiles of basal-like and human epidermal growth factor 2 (HER2)-overexpressing tumors. [Conclusions]: Our results provide evidence that well-defined DNA methylation profiles enable breast cancer subtype prediction and support the utilization of this biomarker for prognostication and therapeutic stratification of patients with breast cancer.This work was supported by grants from project CGL2008-01131 (Departamento de Sanidad del Gobierno Vasco), S-PE08UN45 and PE09BF02 (Departamento de Ciencia y Tecnologia del Gobierno Vasco), BIO2008-04212, and RD06/0020/1019 (Red Tematica de Investigacion Cooperativa en Cancer, RTICC) from the MICINN. The CIBER de Enfermedades Raras is an initiative of the ISCIII. NGB had a doctoral fellowship from the Basque Government (Departamento de Educacion, Universidades e Investigacion).Peer reviewe

An Epigenetic Perspective on Intra-Tumour Heterogeneity: Novel Insights and New Challenges from Multiple Fields

Cancer is a group of heterogeneous diseases that results from the occurrence of genetic alterations combined with epigenetic changes and environmental stimuli that increase cancer cell plasticity. Indeed, multiple cancer cell populations coexist within the same tumour, favouring cancer progression and metastatic dissemination as well as drug resistance, thereby representing a major obstacle for treatment. Epigenetic changes contribute to the onset of intra-tumour heterogeneity (ITH) as they facilitate cell adaptation to perturbation of the tumour microenvironment. Despite being its central role, the intrinsic multi-layered and reversible epigenetic pattern limits the possibility to uniquely determine its contribution to ITH. In this review, we first describe the major epigenetic mechanisms involved in tumourigenesis and then discuss how single-cell-based approaches contribute to dissecting the key role of epigenetic changes in tumour heterogeneity. Furthermore, we highlight the importance of dissecting the interplay between genetics, epigenetics, and tumour microenvironments to decipher the molecular mechanisms governing tumour progression and drug resistance