Eosinophilic Panniculitis and Insect Bite-Like Eruption in a Patient with Chronic Lymphocytic Leukaemia: A Spectrum of the Same Entity

Background. Eosinophilic dermatosis of hematologic disorders is a reactive process that may cause a variety of clinical manifestations. Methods. We report a patient who had outbreaks of skin lesions since the onset of chronic lymphocytic leukaemia. Results. The cutaneous eruptions began as eosinophilic panniculitis and after changed to insect bite-like lesions. Conclusion. We think that eosinophilic panniculitis and insect bite-like lesions may be part of the spectrum of the same entity in patients with hematologic disorders

Hypoacusia in a Patient Treated by Isotretinoin

Isotretinoin is the most effective treatment for severe acne, but there are several adverse effects associated with its use, some of them very exceptional (<1/10000). We report one case of hypoacusia and tinnitus in a 15-year-old boy treated with isotretinoin during 6 weeks, who quickly improved after isotretinoin withdrawal. Also, we comment other publications about hearing alterations in patients treated with isotretinoin and other retinoids

Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer

Altres ajuts: This work was co-finaced by the European Development Regional Fund, "A way to achieve Europe" ERDF; the Cellex Foundation; and "la Caixa" Banking Foundation (LCF/PR/PR15/ 11100003).Human tumors show altered patterns of protein isoforms that can be related to the dysregulation of messenger RNA alternative splicing also observed in transformed cells. Although somatic mutations in core spliceosome components and their associated factors have been described in some cases, almost nothing is known about the contribution of distorted epigenetic patterns to aberrant splicing. Herein, we show that the splicing RNA-binding protein CELF2 is targeted by promoter hypermethylation-associated transcriptional silencing in human cancer. Focusing on the context of breast cancer, we also demonstrate that CELF2 restoration has growth-inhibitory effects and that its epigenetic loss induces an aberrant downstream pattern of alternative splicing, affecting key genes in breast cancer biology such as the autophagy factor ULK1 and the apoptotic protein CARD10. Furthermore, the presence of CELF2 hypermethylation in the clinical setting is associated with shorter overall survival of the breast cancer patients carrying this epigenetic lesion

Restauración, rehabilitación y regeneración: las 3R del completamiento urbano desde la perspectiva del diseño constructivo : Una experiencia de trabajo práctico de integración

La propuesta presenta la experiencia pedagógica desarrollada en un Trabajo Práctico Vertical de Integración (TPVI) en el marco del Taller Vertical Nº 3 de la materia Procesos Constructivos de la carrera de grado de la FAU - UNLP, perteneciente al segundo, tercero y cuarto año de la carrera. La interacción entre los tres niveles de la materia, bajo una misma temática de investigación y aplicación metodológica. Se toma como caso de estudio para el desarrollo del TPVI, la experiencia de “La Casa por el Tejado”, empresa que realiza intervenciones de completamiento urbano construidas sobre las cubiertas de edificios existentes con edificabilidad vacante de acuerdo a la normativa urbanística, en el área del Plan Cerdá -el Ensanche- en la ciudad de Barcelona, España, restaurando y rehabilitando los mismos y promoviendo la regeneración urbana en un área central de la ciudad. En forma previa al inicio del TPVI se realiza una capacitación docente para profundizar sobre el concepto, la tecnología y los sistemas, y acordar un tratamiento común de los ejemplos utilizados. El objetivo general del TPVI es conformar una metodología de abordaje del conocimiento de materiales, técnicas y tecnologías, para aplicar en el análisis de los tres ejes del diseño constructivo en los que se basa la Propuesta Pedagógica del Taller: el eje sistémico, el eje tecnológico y el eje sustentable. En forma particular, se persigue que el estudiante adquiera un lenguaje técnico común; que este lenguaje le aporte precisión en la especificación técnica al definir la materialidad de los distintos subsistemas en la documentación gráfica y escrita de un diseño constructivo, en distintas escalas de complejidad por nivel. El trabajo de 5 clases comienza por un diagnóstico entre los tres niveles del Taller, se identifica una problemática en común que requiere la aplicación de nuevas estrategias pedagógicas que aborden las necesidades del estudiante. Acorde con la propuesta pedagógica del Taller que considera el tema de materiales, elementos y componentes, como un vector que atraviesa los tres niveles, se indaga y estudia el reconocimiento e incidencia de estos en los procesos constructivos, donde cada alumno aporta la mirada propia de su nivel en la implementación del TPVI. Permite, asimismo, enriquecer la experiencia de aprendizaje compartiendo con sus pares los saberes incorporados en años anteriores, así como en otras asignaturas, favoreciendo la construcción de conocimiento colectivo y colaborativo, y su concientización sobre el grado de comprensión alcanzado sobre estos temas, el intercambio de visiones y definiciones constructivas en el desarrollo de un proyecto común.Facultad de Arquitectura y Urbanism

Purification and biochemical characterization of four iron superoxide dismutases in Trypanosoma cruzi

Four superoxide dismutase (SOD) activities (SOD I, II, III, and IV) have been characterized in the epimastigote form of Trypanosoma cruzi . The total extract was subjected to two successive ammonium sulphate additions between 35 and 85%, and the resulting fraction was purified using two continuous chromatography processes (ion exchange and filtration). Enzymes were insensitive to cyanide but sensitive to hydrogen peroxide, properties characteristic of iron-containing SODs. The molecular masses of the different SODs were 20 kDa (SOD I), 60 kDa (SOD II), 50 kDa (SOD III) and 25 kDa (SOD IV), whereas the isoelectric points were 6.9, 6.8, 5.2 and 3.8, respectively. Subcellular location and digitonin experiments have shown that these SODs are mainly cytosolic, with small amounts in the low- mass organelles (SOD II and SOD I) and the mitochondrion (SOD III), where these enzymes play an important role in minimizing oxidative damage.Financial support: CGL2006-27889-E/BOS, Ministerio de Ciencia y Tecnología

Epigenetic loss of RNA‑methyltransferase NSUN5 in glioma targets ribosomes to drive stress adaptive translational program

Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease

Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicenter, retrospective analysis

Background: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC. Methods: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival. Findings: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0·010, 95% CI 3·29 × 10 −4–0·0282; p=0·0067) and overall survival (0·080, 0·017–0·373; p=0·0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0·330, 0·149–0·727; p=0·0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0·415, 0·209–0·802; p=0·0063) and overall survival (0·409, 0·220–0·780; p=0·0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy. Interpretation: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies

Gene Flow in Genetically Modified Wheat

Understanding gene flow in genetically modified (GM) crops is critical to answering questions regarding risk-assessment and the coexistence of GM and non-GM crops. In two field experiments, we tested whether rates of cross-pollination differed between GM and non-GM lines of the predominantly self-pollinating wheat Triticum aestivum. In the first experiment, outcrossing was studied within the field by planting “phytometers” of one line into stands of another line. In the second experiment, outcrossing was studied over distances of 0.5–2.5 m from a central patch of pollen donors to adjacent patches of pollen recipients. Cross-pollination and outcrossing was detected when offspring of a pollen recipient without a particular transgene contained this transgene in heterozygous condition. The GM lines had been produced from the varieties Bobwhite or Frisal and contained Pm3b or chitinase/glucanase transgenes, respectively, in homozygous condition. These transgenes increase plant resistance against pathogenic fungi. Although the overall outcrossing rate in the first experiment was only 3.4%, Bobwhite GM lines containing the Pm3b transgene were six times more likely than non-GM control lines to produce outcrossed offspring. There was additional variation in outcrossing rate among the four GM-lines, presumably due to the different transgene insertion events. Among the pollen donors, the Frisal GM line expressing a chitinase transgene caused more outcrossing than the GM line expressing both a chitinase and a glucanase transgene. In the second experiment, outcrossing after cross-pollination declined from 0.7–0.03% over the test distances of 0.5–2.5 m. Our results suggest that pollen-mediated gene flow between GM and non-GM wheat might only be a concern if it occurs within fields, e.g. due to seed contamination. Methodologically our study demonstrates that outcrossing rates between transgenic and other lines within crops can be assessed using a phytometer approach and that gene-flow distances can be efficiently estimated with population-level PCR analyses

Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program

Altres ajuts: This work was supported by the Obra Social "La Caixa" (to M. Esteller).Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease