Integrated analysis of mismatch repair system in malignant astrocytomas

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.Malignant astrocytomas are the most aggressive primary brain tumors with a poor prognosis despite optimal treatment. Dysfunction of mismatch repair (MMR) system accelerates the accumulation of mutations throughout the genome causing uncontrolled cell growth. The aim of this study was to characterize the MMR system defects that could be involved in malignant astrocytoma pathogenesis. We analyzed protein expression and promoter methylation of MLH1, MSH2 and MSH6 as well as microsatellite instability (MSI) and MMR gene mutations in a set of 96 low- and high-grade astrocytomas. Forty-one astrocytomas failed to express at least one MMR protein. Loss of MSH2 expression was more frequent in low-grade astrocytomas. Loss of MLH1 expression was associated with MLH1 promoter hypermethylation and MLH1 -93G>A promoter polymorphism. However, MSI was not related with MMR protein expression and only 5% of tumors were MSI-High. Furthermore, the incidence of tumors carrying germline mutations in MMR genes was low and only one glioblastoma was associated with Lynch syndrome. Interestingly, survival analysis identified that tumors lacking MSH6 expression presented longer overall survival in high-grade astrocytoma patients treated only with radiotherapy while MSH6 expression did not modify the prognosis of those patients treated with both radiotherapy and chemotherapy. Our findings suggest that MMR system alterations are a frequent event in malignant astrocytomas and might help to define a subgroup of patients with different outcome.This work was supported by Fondo de Investigación Sanitaria (FIS PI 10/00219), Instituto de Estudios de Ciencias de la Salud de Castilla y León IECSCYL and Junta de Castilla y León y Fondo Social Europeo (Orden EDU/330/2008).Peer Reviewe

MicroRNA-223 is a novel negative regulator of HSP90B1 in CLL

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.-- et al.[Background]: MicroRNAs are known to inhibit gene expression by binding to the 3'UTR of the target transcript. Downregulation of miR-223 has been recently reported to have prognostic significance in CLL. However, there is no evidence of the pathogenetic mechanism of this miRNA in CLL patients. [Methods]: By applying next-generation sequencing techniques we have detected a common polymorphism (rs2307842), in 24% of CLL patients, which disrupts the binding site for miR-223 in HSP90B1 3'UTR. We investigated whether miR-223 directly targets HSP90B1 through luciferase assays and ectopic expression of miR-223. Quantitative real-time polymerase chain reaction and western blot were used to determine HSP90B1 expression in CLL patients. The relationship between rs2307842 status, HSP90B1 expression and clinico-biological data were assessed. [Results]: HSP90B1 is a direct target for miR-223 by interaction with the putative miR-223 binding site. The analysis in paired samples (CD19+ fraction cell and non-CD19+ fraction cell) showed that the presence of rs2307842 and IGHV unmutated genes determined HSP90B1 overexpression in B lymphocytes from CLL patients. These results were confirmed at the protein level by western blot. Of note, HSP90B1 overexpression was independently predictive of shorter time to the first therapy in CLL patients. By contrast, the presence of rs2307842 was not related to the outcome. [Conclusions]: HSP90B1 is a direct target gene of miR-223. Our results provide a plausible explanation of why CLL patients harboring miR-223 downregulation are associated with a poor outcome, pointing out HSP90B1 as a new pathogenic mechanism in CLL and a promising therapeutic target.This work was partially supported by grants from the Spanish Fondo de Investigaciones Sanitarias FIS 09/01543 and PI12/00281, Proyectos de Investigación del SACYL 355/A/09, COST Action EuGESMA (BM0801), Fundación Manuel Solórzano, Obra Social Banca Cívica (Caja Burgos), Fundación Española de Hematología y Hemoterapia (FEHH) and by a grant (RD12/0036/0069) from the Red Temática de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness & European Regional Development Fund (ERDF) “Una manera de hacer Europa” (Innocampus). The research leading to these results has received funding from the European Union Seventh Framework Programme [FP7/2007-2013] under Grant Agreement n°306242-NGS-PTL. MHS is fully supported by an Ayuda predoctoral de la Junta de Castilla y Leon by the Fondo Social Europeo. ME Sarasquete is supported by Contrato Miguel Servet (CP13/00080).Peer Reviewe

Hormony tarczycy i otyłość: znana, lecz słabo rozpoznana relacja

Hormony tarczycy (thyroid hormones, TH) są zaangażowane w wiele różnych procesów biologicznych, wliczając rozwój układu nerwowego, regulację metabolizmu pośredniego oraz zużycie energii. Aktywnie uczestniczą w podstawowym zużyciu energii i termogenezie adaptacyjnej i z tego względu mogą mieć wpływ na masę ciała w przebiegu chorób tarczycy. Otyłość to niezakaźna, przewlekła, zapalna choroba metaboliczna, która implikuje dodatni bilans energetyczny. Tkanka tłuszczowa produkuje szereg hormonów i adipocytokin, takich jak leptyna, które mogą wpływać na stan tarczycy na różnych poziomach. Istnieją dowody na to, że dysfunkcja tarczycy może predysponować do otyłości i odwrotnie, istnieją dowody sugerujące, że otyłość powoduje zmiany dotyczące tarczycy. Celem tej pracy było opisanie związku między układem tarczycy a otyłością. Ponadto w pracy zaprezentowano hipotetyczny model podkreślający znaczenie obwodowej dejodynacji hormonów tarczycy i jego rolę w ustanowieniu dodatniego bilansu energetycznego. Podsumowując, możemy stwierdzić, że relacja między układem tarczycy a otyłością i nadwagą jest złożona i obejmuje wiele poziomów interakcji. Ponadto, poddając ocenie otyłego pacjenta, powinno się rozważyć ocenę funkcji tarczycy, aby uzyskać lepsze i spersonalizowane efekty leczenia

Using the new technologies in claudication patients: CReTe: Claudication patients and telematic register

Objetivo: Presentamos una aplicación informática para teléfonos móviles ideada para el control de sesiones de ejercicio domiciliario en claudicantes. Exponemos también nuestros resultados preliminares. Material y métodos: La aplicación está dise˜nada para teléfonos móviles con sistema operativo Android, tecnología de geolocalización y conexión de datos. Está conectada a una base de datos codificada que preserva el secreto médico. Los datos que se recogen de las sesiones de ejercicio son la fecha, la hora de inicio y de fin, el tiempo dedicado, el número de las paradas realizadas y la velocidad máxima, la velocidad media global y la velocidad entre paradas. Durante el mes de enero de 2014 se reclutó a aquellos pacientes que aceptaran el estudio, poseyeran y entendieran un dispositivo móvil Android con geolocalización y conexión de datos. Los criterios de exclusión del estudio una vez comenzado fueron progresión hacia isquemia arterial crítica, enfermedad intercurrente grave, fallecimiento y ausencia de comunicación con el paciente. Se recogieron las principales morbilidades y los resultados de los cuestionarios de calidad de vida SF36 y EuroQol 5D. Se midió el tiempo de primera consulta y el tiempo dedicado por semana y paciente durante un seguimiento de 28 días. Se calculó el cumplimiento de las sesiones con respecto a las sesiones pactadas con cada paciente, con un mínimo de 2 semanales. Resultados: Un total de 5 pacientes fueron incluidos, con edad media de 59,3 a˜nos (mediana 52; rango 40-80). De ellos 2 se excluyeron, uno por progresión a isquemia crítica y otro por ausencia de comunicación. El tiempo medio dedicado por consulta nueva fue de 29,1 min (mediana 27,5; rango 45-20). El cumplimiento de las sesiones fue del 100% en 2 pacientes y del 63% en otro. El tiempo dedicado en el seguimiento semanal por paciente fue de 1,68 min. Conclusiones: CReTe es una herramienta aplicable a nuestro medio que precisa de estudios mayores para demostrar su utilidad.Objective: The preliminary results are presented on the use of a new application for mobile phones designed to control home exercise sessions in claudication.Materials and methods: The application is designed for Android systems with geolocation tech-nology and Internet connection. It is connected to a database encoded to ensure medical confidentiality. The data collected from the exercise sessions were the date, start time and end time, the time spent, the number of stops made, and the maximum speed, average speed and overall speed between stops. During the month of January 2014 patients who accepted and understood the study, and possessed an Android mobile device with geolocation and data connection, were enrolled. The exclusion criteria, 11 the study started, were progression to arterial ischemia, severe intercurrent illness, non-communication with the patient, and death. Major morbidities and results of quality of life questionnaires SF36 and EuroQol 5 D were collec-ted. Time of first consultation and time spent per week per patient during a 28-day follow-up was recorded. Compliance as regards the agreed sessions was calculated for each patient, with a minimum of 2 weeks.Results: The study included 5 patients with a mean age 59.3 years (median 52; range 40-80). Of these, 2 were excluded, one for progression to critical ischemia and another for non-communication. The average time spent in a new consultation was 29.1 minutes (median 27.5, range 45-20). The compliance with the sessions was 100% in 2 patients, and 63% in another. Time spent in the weekly monitoring per patient was 1.68 minutes.Conclusions: CReTe is an applicable tool in our environment that requires further study to demonstrate its usefulness

Pathogenic convergence of CNVs in genes functionally associated to a severe neuromotor developmental delay syndrome.

Background Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations that are likely to contribute to the full neurological phenotype as a consequence of pathogenic gene combinations. Methods To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single-nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs). Results The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission, and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient. Conclusions Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.post-print783 K

Integrative analysis of DNA copy number, DNA methylation and gene expression in multiple myeloma reveals alterations related to relapse

Multiple myeloma (MM) remains incurable despite the introduction of novel agents, and a relapsing course is observed in most patients. Although the development of genomic technologies has greatly improved our understanding of MM pathogenesis, the mechanisms underlying relapse have been less thoroughly investigated. In this study, an integrative analysis of DNA copy number, DNA methylation and gene expression was conducted in matched diagnosis and relapse samples from MM patients. Overall, the acquisition of abnormalities at relapse was much more frequent than the loss of lesions present at diagnosis, and DNA losses were significantly more frequent in relapse than in diagnosis samples. Interestingly, copy number abnormalities involving more than 100 Mb of DNA at relapse significantly affect the gene expression of these samples, provoking a particular deregulation of the IL-8 pathway. On the other hand, no significant modifications of gene expression were observed in those samples with less than 100 Mb affected by chromosomal changes. Although several statistical approaches were used to identify genes whose abnormal expression at relapse was regulated by methylation, only two genes that were significantly deregulated in relapse samples (SORL1 and GLT1D1) showed a negative correlation between methylation and expression. Further analysis revealed that DNA methylation was involved in regulating SORL1 expression in MM. Finally, relevant changes in gene expression observed in relapse samples, such us downregulation of CD27 and P2RY8, were most likely not preceded by alterations in the corresponding DNA. Taken together, these results suggest that the genomic heterogeneity described at diagnosis remains at relapse.This work was partially supported by the Instituto de Salud Carlos III-Cofinanciación con fondos FEDER (PI080568, PS0901897 and PI13/00111), the Gerencia Regional de Salud, Junta de Castilla y León (GRS202/A08 and GRS 702/A/11), the Spanish Myeloma Network Program (RD06/0020/0006) and the Asociación Española Contra el Cáncer (AECC, GCB120981SAN).Peer Reviewe

TET2 overexpression in chronic lymphocytic leukemia is unrelated to the presence of TET2 variations

This is an open access article distributed under the Creative Commons Attribution License.TET2 is involved in a variety of hematopoietic malignancies, mainly in myeloid malignancies. Most mutations of TET2 have been identified in myeloid disorders, but some have also recently been described in mature lymphoid neoplasms. In contrast to the large amount of data about mutations of TET2, some data are available for gene expression. Moreover, the role of TET2 in chronic lymphocytic leukemia (CLL) is unknown. This study analyzes both TET2 expression and mutations in 48 CLL patients. TET2 expression was analyzed by exon arrays and quantitative real-time polymerase chain reaction (qRT-PCR). Next-generation sequencing (NGS) technology was applied to investigate the presence of TET2 variations. Overexpression of TET2 was observed in B-cell lymphocytes from CLL patients compared with healthy donors (P = 0.004). In addition, in CLL patients, an overexpression of TET2 was also observed in the clonal B cells compared with the nontumoral cells (P = 0.002). However, no novel mutations were observed. Therefore, overexpression of TET2 in CLL seems to be unrelated to the presence of genomic TET2 variations.This work was partially supported by Grants from the Spanish Fondo de Investigaciones Sanitarias FIS 09/01543, PI12/00281, Proyectos de Investigacion del SACYL 355/A/09, COST Action “EuGESMA” (BM0801), Fundación “Manuel Solorzano,” Obra Social Banca Cívica (Caja Burgos), Fundacion Española de Hematología y Hemoterapia (FEHH), and by a Grant (RD12/0036/0069) from Red Temática de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness and European Regional Development Fund (ERDF) “Una manera de hacer Europa”, and NGS-PTL no. 306242. Maríıa Hernandez-Sánchez is fully suported by an “Ayuda predoctoral de la Junta de Castilla y Leon” by the “Fondo Social Europeo.”Peer Reviewe

Resilience of small-scale societies’ livelihoods: a framework for studying the transition from food gathering to food production

The origins of agriculture and the shift from hunting and gathering to committed agriculture is regarded as one of the major transitions in human history. Archeologists and anthropologists have invested significant efforts in explaining the origins of agriculture. A period of gathering intensification and experimentation and pursuing a mixed economic strategy seems the most plausible explanation for the transition to agriculture and provides an approach to study a process in which several nonlinear processes may have played a role. However, the mechanisms underlying the transition to full agriculture are not completely clear. This is partly due to the nature of the archeological record, which registers a practice only once it has become clearly established. Thus, points of transitions have limited visibility and the mechanisms involved in the process are difficult to untangle. The complexity of such transitions also implies that shifts can be distinctively different in particular environments and under varying historical and social conditions. In this paper we discuss some of the elements involved in the transition to food production within the framework of resilience theory. We propose a theoretical conceptual model in which the resilience of livelihood strategies lies at the intersection of three spheres: the environmental, economical, and social domains. Transitions occur when the rate of change, in one or more of these domains, is so elevated or its magnitude so large that the livelihood system is unable to bounce back to its original state. In this situation, the system moves to an alternative stable state, from one livelihood strategy to another.This paper is the result of a two-day workshop funded by ICREA (Catalan Higher Research Institution) and organized at the ICTA (Institute for Environmental Studies) of the Autonomous University of Barcelona and the Department of Humanities of the Universitat Pompeu Fabra. The workshop was cofounded by the SimulPast project (former Spanish Ministry of Science and Innovation, CSD2010-00034). CL, DZ, MM, and JJGG are part of CaSEs (Complexity and Socio-Ecological Dynamics Research Group), a Grup de Recerca Emergent of the Generalitat de Catalunya (SGR-e 1417). CL is currently a UPFellow; JJGG was supported by a JAE PreDOC PhD scholarship (Spanish National Research Council and European Social Fund) and the SimulPast project.Peer Reviewe

Understanding why women don’t choose engineering degrees

Despite the continuous efforts of governments and universities to avoid the underrepresentation of women entering engineering degrees, the trend has not reverted, and this is a general fact all over the world. This fact goes against the tendency of a growing ratio of women in tertiary education, so causes must be investigated. This research examines two main questions: Is it possible to break the invisible barriers that prevent girls from entering in engineering degrees by means of an engineering project or activity? And are there important misconceptions about the role of women in engineering professions and about engineering itself among high school girls? An extensive survey has been carried out between three groups of students: students of the last years of high school (834), students of the first year of engineering degrees (319), and students of the first year of sciences degrees (209). A set of visits to the high schools was developed and a contest of engineering projects was carried out too. The results show that there are important misconceptions in the knowledge that high school students have about engineering degrees and engineering. The visits and the project contest had a good impact that encouraged girls to take engineering activities in their curricula. The main finding is that even though girls see engineering professions as very well valued, they are convinced that engineering is not a profession for women, which suggests that there are educational barriers acquired during earlier stages of their lives