Distinction between asymptomatic monoclonal B-cell lymphocytosis with cyclin D1 overexpression and mantle cell lymphoma: from molecular profiling to flow cytometry

PMCID: PMC4488901.-- et al.[Purpose]: According to current diagnostic criteria, mantle cell lymphoma (MCL) encompasses the usual, aggressive variants and rare, nonnodal cases with monoclonal asymptomatic lymphocytosis, cyclin D1- positive (MALD1). We aimed to understand the biology behind this clinical heterogeneity and to identify markers for adequate identification of MALD1 cases. [Experimental Design]: We compared 17 typical MCL cases with a homogeneous group of 13 untreated MALD1 cases (median follow-up, 71 months). We conducted gene expression profiling with functional analysis in five MCL and five MALD1. Results were validated in 12 MCL and 8 MALD1 additional cases by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in 24MCLand 13MALD1 cases by flow cytometry. Classification and regression trees strategy was used to generate an algorithm based on CD38 and CD200 expression by flow cytometry. [Results]: We found 171 differentially expressed genes with enrichment of neoplastic behavior and cell proliferation signatures in MCL. Conversely, MALD1 was enriched in gene sets related to immune activation and inflammatory responses. CD38 and CD200 were differentially expressed betweenMCLandMALD1and confirmed by flow cytometry (median CD38, 89% vs. 14%; median CD200, 0% vs. 24%, respectively). Assessment of both proteins allowed classifying 85% (11 of 13) of MALD1 cases whereas 15% remained unclassified. SOX11 expression by qRT-PCR was significantly different between MCL and MALD1 groups but did not improve the classification. [Conclusion]: We show for the first time that MALD1, in contrast to MCL, is characterized by immune activation and driven by inflammatory cues. Assessment of CD38/CD200 by flow cytometry is useful to distinguish most cases of MALD1 from MCL in the clinical setting. MALD1 should be identified and segregated from the current MCL category to avoid overdiagnosis and unnecessary treatment.This work has been supported, in part, by grants from Instituto de Salud Carlos III RD07/0020/2004, RD09/0076/00036, RD12/0036/0044, (RTICC, FEDER), Generalitat de Catalunya 2009/SGR541, and the “Xarxa de Bancs de Tumors” sponsored by Pla Director d'Oncologia de Catalunya (XBTC).Peer Reviewe

O emprego precário de jovens assalariados no México. o caso de Toluca, Tijuana e Mérida (2005 - 2010)

Globalization and productive restructuration have set a new dynamic in labor markets worldwide. This new labor context is characterized by precarious labor conditions, phenomenon that is not exclusive of any population sector but affects them in a differential way, young people being the most vulnerable group. This article aim is to analyze the labor conditions of young workers population in three Mexican cities: Toluca, Tijuana and Merida. For this purpose, a precarious labor rate was estimated for all three cities for the first quarter of 2005 and 2010. Results show that Toluca city has the highest share of young people in precarious jobs, against Tijuana city where there are better conditions.La globalización y la reestructuración productiva han configurado una nueva dinámica en los mercados de trabajo a nivel mundial. Este nuevo contexto laboral está caracterizado por la precarización de las condiciones laborales, fenómeno que no es exclusivo de algún sector de la población pero que los afecta de manera diferenciada, siendo los jóvenes uno de los grupos más vulnerables. El objetivo de este artículo es analizar las condiciones laborales de la población joven asalariada de tres ciudades mexicanas: Toluca, Tijuana y Mérida. Para ello, se estimó para estas tres ciudades un índice de precariedad laboral para el primer trimestre de 2005 y 2010. Los resultados muestran que la ciudad de Toluca registra una mayor proporción de jóvenes en empleos precarios, contra la ciudad de Tijuana donde se registran mejores condiciones laborales.A globalização e a reestruturação produtiva configuraram uma nova dinâmica nos mercados de trabalho a nível mundial. Este novo contexto laboral está caracterizado pela precarização das condições de trabalho, fenômeno que não é exclusivo de um setor em especial da população, mas que os afeta a todos de maneira diferenciada, sendo os jovens um dos grupos mais vulneráveis. O objetivo deste artigo é analisar as condições laborais da população jovem assalariada de três cidades mexicanas: Toluca, Tijuana e Mérida. Para isso, estimou-se para estas três cidades um índice de precariedade laboral para o primeiro trimestre de 2005 e 2010. Os resultados mostram que a cidade de Toluca registra uma maior proporção de jovens em empregos precários, em relação à cidade de Tijuana onde se registram melhores condições de trabalho

Las políticas activas de empleo en México: el caso de los programas de formación

En las últimas décadas las políticas activas de empleo han cobrado gran relevancia en el impulso y mejora de la empleabilidad de las personas. En particular, las políticas de empleo en México han atravesado por una serie de transformaciones, por lo cual en este documento se hace una análisis teórico y empírico de su estructura y evolución, con el objetivo de responder básicamente dos preguntas que son: ¿cuáles han sido los impactos de las políticas de formación en México en el periodo de 2000 a 2010? y ¿qué factores están asociados a la mejora de la empleabilidad de los beneficiarios de los programas de formación?. Para responder esta última pregunta se elabora un modelo logístico para los beneficiarios de los programas de formación en México del año 2008. El modelo realizado nos permite establecer qué características asociadas al individuo son determinantes en la mejora de la empleabilidad, lo cual puede ser de utilidad en la focalización de las políticas de formación.ABSTRACTIn last decades, the active labor market policies have become an important instrument to promote and improve the employability of the active population. In México, the active labor market policies has experimented transformations in its structure and evolution, in these sense, the objective of this paper is answer two basic questions: What has been the impacts of the active labor market policies in México from 2000 to 2010? And, What factors are related to improve the employability of the training programs?.To answer the last question, a logistic model is made based on the data of beneficiaries of training programs in Mexico in 2008. The model allows determinate the individual characteristics associated in the improvement of employability, which could be useful on targeting training policies.  &nbsp

oPOSSUM: identification of over-represented transcription factor binding sites in co-expressed genes

Targeted transcript profiling studies can identify sets of co-expressed genes; however, identification of the underlying functional mechanism(s) is a significant challenge. Established methods for the analysis of gene annotations, particularly those based on the Gene Ontology, can identify functional linkages between genes. Similar methods for the identification of over-represented transcription factor binding sites (TFBSs) have been successful in yeast, but extension to human genomics has largely proved ineffective. Creation of a system for the efficient identification of common regulatory mechanisms in a subset of co-expressed human genes promises to break a roadblock in functional genomics research. We have developed an integrated system that searches for evidence of co-regulation by one or more transcription factors (TFs). oPOSSUM combines a pre-computed database of conserved TFBSs in human and mouse promoters with statistical methods for identification of sites over-represented in a set of co-expressed genes. The algorithm successfully identified mediating TFs in control sets of tissue-specific genes and in sets of co-expressed genes from three transcript profiling studies. Simulation studies indicate that oPOSSUM produces few false positives using empirically defined thresholds and can tolerate up to 50% noise in a set of co-expressed genes

In Silico Detection of Sequence Variations Modifying Transcriptional Regulation

Identification of functional genetic variation associated with increased susceptibility to complex diseases can elucidate genes and underlying biochemical mechanisms linked to disease onset and progression. For genes linked to genetic diseases, most identified causal mutations alter an encoded protein sequence. Technological advances for measuring RNA abundance suggest that a significant number of undiscovered causal mutations may alter the regulation of gene transcription. However, it remains a challenge to separate causal genetic variations from linked neutral variations. Here we present an in silico driven approach to identify possible genetic variation in regulatory sequences. The approach combines phylogenetic footprinting and transcription factor binding site prediction to identify variation in candidate cis-regulatory elements. The bioinformatics approach has been tested on a set of SNPs that are reported to have a regulatory function, as well as background SNPs. In the absence of additional information about an analyzed gene, the poor specificity of binding site prediction is prohibitive to its application. However, when additional data is available that can give guidance on which transcription factor is involved in the regulation of the gene, the in silico binding site prediction improves the selection of candidate regulatory polymorphisms for further analyses. The bioinformatics software generated for the analysis has been implemented as a Web-based application system entitled RAVEN (regulatory analysis of variation in enhancers). The RAVEN system is available at http://www.cisreg.ca for all researchers interested in the detection and characterization of regulatory sequence variation

Principles of precision medicine in stroke

The era of precision medicine has arrived and conveys tremendous potential, particularly for stroke neurology. The diagnosis of stroke, its underlying aetiology, theranostic strategies, recurrence risk and path to recovery are populated by a series of highly individualised questions. Moreover, the phenotypic complexity of a clinical diagnosis of stroke makes a simple genetic risk assessment only partially informative on an individual basis. The guiding principles of precision medicine in stroke underscore the need to identify, value, organise and analyse the multitude of variables obtained from each individual to generate a precise approach to optimise cerebrovascular health. Existing data may be leveraged with novel technologies, informatics and practical clinical paradigms to apply these principles in stroke and realise the promise of precision medicine. Importantly, precision medicine in stroke will only be realised once efforts to collect, value and synthesise the wealth of data collected in clinical trials and routine care starts. Stroke theranostics, the ultimate vision of synchronising tailored therapeutic strategies based on specific diagnostic data, demand cerebrovascular expertise on big data approaches to clinically relevant paradigms. This review considers such challenges and delineates the principles on a roadmap for rational application of precision medicine to stroke and cerebrovascular health

Active unilateral condylar hyperplasia : assessment of the usefulness of single photon emission computed tomography

This study aims to evaluate whether the uptake difference by the condyles evaluated using single photon emission computed tomography (SPECT) examination is useful for predicting the activity of the feature and the advance of this pathology. An observational and prospective study has been carried out on nine patients affected by unilateral condylar hyperplasia (UCH) with complete bone maturation, with a follow-up over 18 months. At the beginning of the study, a test-battery was conducted including dental casts, articular examination, teleradiography and cephalometry, computed tomography and SPECT, creating two groups of patients from a difference in uptake between both condyles greater than 10% over the follow-up period. Evolution of data obtained with the rest of the diagnostic tests were compared to confirm UCH activity predicted by SPECT. The comparison of both groups did not show hardly any significant differences, with little clinical significance. Deviation of the mandibular line, the size of the branches or condyles behaved similarly in both study groups. From the data obtained in our study, we can conclude that the use of the difference in uptake between both condyles by applying the SPECT technique is not a valid approach for predicting clinical activity in cases of UCH

Stimuli Characteristics and Psychophysical Requirements for Visual Training in Amblyopia: A Narrative Review

Active vision therapy using perceptual learning and/or dichoptic or binocular environments has shown its potential effectiveness in amblyopia, but some doubts remain about the type of stimuli and the mode and sequence of presentation that should be used. A search was performed in PubMed, obtaining 143 articles with information related to the stimuli used in amblyopia rehabilitation, as well as to the neural mechanisms implied in such therapeutic process. Visual deficits in amblyopia and their neural mechanisms associated are revised, including visual acuity loss, contrast sensitivity reduction and stereopsis impairment. Likewise, the most appropriate stimuli according to the literature that should be used for an efficient rehabilitation of the amblyopic eye are described in detail, including optotypes, Gabor’s patches, random-dot stimuli and Vernier’s stimuli. Finally, the properties of these stimuli that can be modified during the visual training are discussed, as well as the psychophysical method of their presentation and the type of environment used (perceptual learning, dichoptic stimulation or virtual reality). Vision therapy using all these revised concepts can be an effective option for treating amblyopia or accelerating the treatment period when combining with patching. It is essential to adapt the stimuli to the patient’s individual features in both monocular and binocular training.The authors C.J.H.-R., D.P.P., A.M.-M., D.d.F., L.L.-V., M.B.C.-M. have been funded by CDTI (Centro para el Desarrollo Tecnológico Industrial, Ministry of Economy and Competitiveness of Spain) and FEDER (Fondos Europeos de Desarrollo Regional) funds by means of the program PID (“Proyectos de Investigación y Desarrollo”) in the context of the Project NEIVATECH (“Neuroplasticity through virtual reality for amblyopia”, application number 111705). The author León Morales-Quezada is supported by funding from the Spaulding Research Catalyst award. The author David P Piñero has been also supported by the Ministry of Economy, Industry and Competitiveness of Spain within the program Ramón y Cajal, RYC-2016-20471

JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles.

International audienceJASPAR (http://jaspar.genereg.net) is an open-access database storing curated, non-redundant transcription factor (TF) binding profiles representing transcription factor binding preferences as position frequency matrices for multiple species in six taxonomic groups. For this 2016 release, we expanded the JASPAR CORE collection with 494 new TF binding profiles (315 in vertebrates, 11 in nematodes, 3 in insects, 1 in fungi and 164 in plants) and updated 59 profiles (58 in vertebrates and 1 in fungi). The introduced profiles represent an 83% expansion and 10% update when compared to the previous release. We updated the structural annotation of the TF DNA binding domains (DBDs) following a published hierarchical structural classification. In addition, we introduced 130 transcription factor flexible models trained on ChIP-seq data for vertebrates, which capture dinucleotide dependencies within TF binding sites. This new JASPAR release is accompanied by a new web tool to infer JASPAR TF binding profiles recognized by a given TF protein sequence. Moreover, we provide the users with a Ruby module complementing the JASPAR API to ease programmatic access and use of the JASPAR collection of profiles. Finally, we provide the JASPAR2016 R/Bioconductor data package with the data of this release

JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles.

International audienceJASPAR (http://jaspar.genereg.net) is an open-access database storing curated, non-redundant transcription factor (TF) binding profiles representing transcription factor binding preferences as position frequency matrices for multiple species in six taxonomic groups. For this 2016 release, we expanded the JASPAR CORE collection with 494 new TF binding profiles (315 in vertebrates, 11 in nematodes, 3 in insects, 1 in fungi and 164 in plants) and updated 59 profiles (58 in vertebrates and 1 in fungi). The introduced profiles represent an 83% expansion and 10% update when compared to the previous release. We updated the structural annotation of the TF DNA binding domains (DBDs) following a published hierarchical structural classification. In addition, we introduced 130 transcription factor flexible models trained on ChIP-seq data for vertebrates, which capture dinucleotide dependencies within TF binding sites. This new JASPAR release is accompanied by a new web tool to infer JASPAR TF binding profiles recognized by a given TF protein sequence. Moreover, we provide the users with a Ruby module complementing the JASPAR API to ease programmatic access and use of the JASPAR collection of profiles. Finally, we provide the JASPAR2016 R/Bioconductor data package with the data of this release