Metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in Chronic myeloid leukemia

Tyrosine kinase inhibitors (TKIs) are currently the standard chemotherapeutic agents for the treatment of chronic myeloid leukemia (CML). However, due to TKI resistance acquisition in CML patients, identification of new vulnerabilities is urgently required for a sustained response to therapy. In this study, we have investigated metabolic reprogramming induced by TKIs independent of BCR-ABL1 alterations. Proteomics and metabolomics profiling of imatinib-resistant CML cells (ImaR) was performed. KU812 ImaR cells enhanced pentose phosphate pathway, glycogen synthesis, serine-glycine-one-carbon metabolism, proline synthesis and mitochondrial respiration compared with their respective syngeneic parental counterparts. Moreover, the fact that only 36% of the main carbon sources were utilized for mitochondrial respiration pointed to glycerol-phosphate shuttle as mainly contributors to mitochondrial respiration. In conclusion, CML cells that acquire TKIs resistance present a severe metabolic reprogramming associated with an increase in metabolic plasticity needed to overcome TKI-induced cell death. Moreover, this study unveils that KU812 Parental and ImaR cells viability can be targeted with metabolic inhibitors paving the way to propose novel and promising therapeutic opportunities to overcome TKI resistance in CML

Implications of the use of organic fertilizers for antibiotic resistance gene distribution in agricultural soils and fresh food products. A plot-scale study

The spread of antibiotic resistance genes (ARG) into agricultural soils, products, and foods severely limits the use of organic fertilizers in agriculture. In order to help designing agricultural practices that minimize the spread of ARG, we fertilized, sown, and harvested lettuces and radish plants in experimental land plots for two consecutive agricultural cycles using four types of fertilizers: mineral fertilization, sewage sludge, pig slurry, or composted organic fraction of municipal solid waste. The analysis of the relative abundances of more than 200,000 ASV (Amplicon Sequence Variants) identified a small, but significant overlap (<10%) between soil's and fertilizer microbiomes. Clinically relevant ARG were found in higher loads (up to 100 fold) in fertilized soils than in the initial soil, particularly in those treated with organic fertilizers, and their loads grossly correlated to the amount of antibiotic residues found in the corresponding fertilizer. Similarly, low, but measurable ARG loads were found in lettuce (tetM, sul1) and radish (sul1), corresponding the lowest values to samples collected from minerally fertilized fields. Comparison of soil samples collected along the total period of the experiment indicated a relatively year-round stability of soil microbiomes in amended soils, whereas ARG loads appeared as unstable and transient. The results indicate that ARG loads in soils and foodstuffs were likely linked to the contribution of bacteria from organic fertilizer to the soil microbiomes, suggesting that an adequate waste management and good pharmacological and veterinarian practicesmay significantly reduce the presence of these ARGs in agricultural soils and plant products.Postprint (published version

Ecotypic differentiation and phenotypic plasticity combine to enhance the invasiveness of the most widespread daisy in Chile, Leontodon saxatilis

Dispersal and reproductive traits of successful plant invaders are expected to undergo strong selection during biological invasions. Numerous Asteraceae are invasive and display dimorphic fruits within a single flower head, resulting in differential dispersal pathways - wind-dispersed fruits vs. nondispersing fruits. We explored ecotypic differentiation and phenotypic plasticity of seed output and fruit dimorphisms in exotic Chilean and native Spanish populations of Leontodon saxatilis subsp. rothii. We collected flower heads from populations in Spain and Chile along a rainfall gradient. Seeds from all populations were planted in reciprocal transplant trials in Spain and Chile to explore their performance in the native and invasive range. We scored plant biomass, reproductive investment and fruit dimorphism. We observed strong plasticity, where plants grown in the invasive range had much greater biomass, flower head size and seed output, with a higher proportion of wind-dispersed fruits, than those grown in the native range. We also observed a significant ecotype effect, where the exotic populations displayed higher proportions of wind-dispersed fruits than native populations. Together, these patterns reflect a combination of phenotypic plasticity and ecotypic differentiation, indicating that Leontodon saxatilis has probably increased propagule pressure and dispersal distances in its invasive range to enhance its invasiveness

Hepatic cyclooxygenase-2 expression protects against diet-induced steatosis, obesity and insulin resistance

Resumen del póster presentado a la Conferencia: FASEB SRC: Liver Biology: Fundamental Mechanisms and Translational Applications, celebrada en Keystone-Colorado (US) del 6 al 11 de julio de 2014.[Background and Aims: Accumulation evidence links obesity-induced inflammation as an important contributor to the induction of insulin resistance. Moreover, insulin resistance plays a key role in the pathophysiology of obesity-related diseases such as type 2 diabetes and non alcoholic fatty liver disease. Cyclooxygenase-1 and -2 catalyze the first step in prostanoid biosynthesis. Since adult hepatocytes fail to induce COX-2 expression regardless of the pro-inflammatory factors used, we have evaluated whether this lack of expression under mild pro-inflammatory conditions might constitute a permissive condition for the onset of insulin resistance. [Methods]: We evaluated the role of COX-2 expression in hepatocytes in a model of insulin resistance and altered energy homeostasis induced by high fat diet by metabolic parameters in transgenic mice constitutively expressing human COX-2 in hepatocytes. [Results]: COX-2 expression in hepatocytes protects from high fat diet-induced hepatic steatosis, obesity and hence insulin resistance, as demonstrated by a decreased hepatic steatosis, adiposity and adipocyte area, an enhanced insulin sensitivity and glucose tolerance, decreased plasmatic and hepatic triglycerides and free fatty acids levels, increased adiponectin/leptin ratio and decreased levels of pro-inflammatory cytokines. COX-2 transgenic mice exhibited increased whole body energy expenditure and fatty acid oxidation. Moreover, when hepatic insulin signaling was analyzed, an increase in insulin receptor-mediated Akt phosphorylation was found in hCOX-2 transgenic mice. Similar results were obtained in human and murine hepatic cells expressing a COX-2 transgene. [Conclusion]: Constitutively expression of COX-2 in hepatocytes protects against adiposity, inflammation and hepatic insulin resistance in mice under high fat diet.Peer Reviewe

Hacer aprendiendo, aprender haciendo: comunidades de aprendizaje-servicio en torno a los malestares de género en la Universidad

Resultados del proyecto "Hacer aprendiendo, aprender haciendo: comunidades de aprendizaje-servicio en torno a los malestares de género en la Universidad" en el que a través de las metodologías que aparecen en el título se generó un co-laboratorio/Asamblea de Facultad de diagnóstico, apoyo y acompañamiento en los malestares de género y acosos en el ámbito universitario. El resultado final fue la promoción de un espacio horizontal en el que las ecologías de saberes de sus integrantes (docentes, estudiantes y PAS) se puso al servicio de la propia comunidad para articular formas de denuncia y acompañamiento

Hepatitis B surface antigen loss after discontinuing nucleos(t)ide analogue for treatment of chronic hepatitis B patients is persistent in White patients

[Objective]: The objective of this study was to determine the long-term clinical outcome and persistence of hepatitis B surface antigen (HBsAg) loss after discontinuation of treatment. [Background]: The prognosis of patients with chronic hepatitis B (CHB) treated with nucleos(t)ide analogues (NAs) who discontinue treatment after loss of HBsAg remains largely unknown, particularly in White patients. [Patients and methods]: We analysed a cohort of patients with CHB who discontinued NA treatment after loss of HBsAg. A total of 69 patients with hepatitis-B-e antigen-positive or hepatitis-B-e antigen-negative CHB with undetectable HBsAg during NA treatment were included after discontinuation of treatment, and followed up for a median period of 37.8 months (interquartile range: 23.8–54.6 months). [Results]: At the end of follow-up, none of the patients showed spontaneous reappearance of HBsAg and only one patient had detectable hepatitis B virus DNA (22 IU/ml). Another patient negative for HBsAg and anti-HBs developed hepatitis B virus reactivation without elevated transaminases after treatment with corticosteroids and vincristine for dendritic cell neoplasm, 38 months after withdrawal of the antiviral treatment. Regarding clinical outcome, a patient with cirrhosis developed hepatocellular carcinoma, 6.6 years after discontinuing treatment. None of the patients had hepatic decompensation or underwent liver transplantation. [Conclusion]: HBsAg clearance after discontinuing NAs in patients with CHB is persistent and associated with good prognosis. The risk for developing hepatocellular carcinoma persists among patients with cirrhosis

Intra and Inter-Observer Reliability and Repeatability of Metatarsus Adductus Angle in Recreational Football Players: A Concordance Study

Metatarsus adductus (MA) is a congenital foot deformity often unrecognized at birth. There is adduction of the metatarsals, supination of the subtalar joint, and plantarflexion of the first ray. The aims of this study were to assess the intra and inter-reader reliability of the radiographic MA measurement angles used in the literature. Methods: All consecutive recreational football players who practice activity more than 5 h/week over 21 years of age with MA by roentgenographic evaluation on weight-bearing dorsoplantar images were included in a cross-sectional study. Controls were matched to cases according to age and gender. We assess all radiographic measurements to evaluate metatarsus adductus with the different measurements frequently used in the literature: Sgarlato, modified Sgarlato, Rearfoot, Root, Engel, modified Engel, Kite, Kilmartin, modified Kilmartin, Simons, and Laaveg & Ponseti. Results: The variables measured in 80 weight-bearing dorsoplantar foot radiographs show excellent reliability ranging p > 0.900 in Sgarlato and modified Sgarlato with low SEM, CV, and MCD. Rearfoot, Root, Engel, modified Engel, Kite, Kilmartin, Simons, Laaveg & Ponseti, and modified Kilmartin’s angles showed intra or inter reliability with ICC lower than <0.900, systematic differences between intersession or inter observers, or high MCD value. Conclusion: It is more suitable to measure the MA angle with the Sgarlato and modified Sgarlato techniques to show higher reliability and repeatability for intra and inter-observer