Mir-21-Sox2 Axis Delineates Glioblastoma Subtypes with Prognostic Impact.

UNLABELLED: Glioblastoma (GBM) is the most aggressive human brain tumor. Although several molecular subtypes of GBM are recognized, a robust molecular prognostic marker has yet to be identified. Here, we report that the stemness regulator Sox2 is a new, clinically important target of microRNA-21 (miR-21) in GBM, with implications for prognosis. Using the MiR-21-Sox2 regulatory axis, approximately half of all GBM tumors present in the Cancer Genome Atlas (TCGA) and in-house patient databases can be mathematically classified into high miR-21/low Sox2 (Class A) or low miR-21/high Sox2 (Class B) subtypes. This classification reflects phenotypically and molecularly distinct characteristics and is not captured by existing classifications. Supporting the distinct nature of the subtypes, gene set enrichment analysis of the TCGA dataset predicted that Class A and Class B tumors were significantly involved in immune/inflammatory response and in chromosome organization and nervous system development, respectively. Patients with Class B tumors had longer overall survival than those with Class A tumors. Analysis of both databases indicated that the Class A/Class B classification is a better predictor of patient survival than currently used parameters. Further, manipulation of MiR-21-Sox2 levels in orthotopic mouse models supported the longer survival of the Class B subtype. The MiR-21-Sox2 association was also found in mouse neural stem cells and in the mouse brain at different developmental stages, suggesting a role in normal development. Therefore, this mechanism-based classification suggests the presence of two distinct populations of GBM patients with distinguishable phenotypic characteristics and clinical outcomes. SIGNIFICANCE STATEMENT: Molecular profiling-based classification of glioblastoma (GBM) into four subtypes has substantially increased our understanding of the biology of the disease and has pointed to the heterogeneous nature of GBM. However, this classification is not mechanism based and its prognostic value is limited. Here, we identify a new mechanism in GBM (the miR-21-Sox2 axis) that can classify ∼50% of patients into two subtypes with distinct molecular, radiological, and pathological characteristics. Importantly, this classification can predict patient survival better than the currently used parameters. Further, analysis of the miR-21-Sox2 relationship in mouse neural stem cells and in the mouse brain at different developmental stages indicates that miR-21 and Sox2 are predominantly expressed in mutually exclusive patterns, suggesting a role in normal neural development

Tripodal amphiphilic pseudopeptidic nanovesicles as p-coumaric acid delivery systems for brain cancer cells

Nanovesicles based on tripodal amphiphilic pseudopeptides are prepared as carriers for p-coumaric acid (p-CA) delivery. Loaded nanovesicles are obtained by both thin film hydration and ethanol injection methods with positive Z-potential values. The last technique renders lower particle sizes and excellent polydispersity index, with average values of 130 nm and 0.123, respectively, although the drug loading obtained after ultracentrifugation is lower. In vitro release experiments, including the use of different external stimuli such as pH and proteolytic enzymes, provide interesting results. The prepared nanovesicles are tested on normal cells (VERO), displaying a high safety profile scoring with a 50% inhibitory concentration (IC50) of 1,822 mg/mL. A 40-times increase in the in vitro cytotoxic effect of p-CA on Glioma GL261 brain cancer cells, from IC50 1,082 mg/mL to 29 mg/mL, is observed using the loaded pseudopeptide nanovesicles. 1 H NMR studies reveal that the drug is mainly located inside the nanoparticle bilayer. Transmembrane carboxyfluorescein studies reveal that the amphiphilic compound does not provide a significant membrane fluidification. Experimental data suggest that the observed biological activity can be associated to an enhanced permeability and retention effect. The present results highlight the potential of such nanovesicles as potent p-CA carriers for brain cancer therapy

Biotechnology approaches to overcome biotic and abiotic stress constraints in legumes

Biotic and abiotic stresses cause significant yield losses in legumes and can significantly affect their productivity. Biotechnology tools such as marker-assisted breeding, tissue culture, in vitro mutagenesis and genetic transformation can contribute to solve or reduce some of these constraints. However, only limited success has been achieved so far. The emergence of “omic” technologies and the establishment of model legume plants such as Medicago truncatula and Lotus japonicus are promising strategies for understanding the molecular genetic basis of stress resistance, which is an important bottleneck for molecular breeding. Understanding the mechanisms that regulate the expression of stress-related genes is a fundamental issue in plant biology and will be necessary for the genetic improvement of legumes. In this review, we describe the current status of biotechnology approaches in relation to biotic and abiotic stresses in legumes and how these useful tools could be used to improve resistance to important constraints affecting legume crops.E. Prats is funded by an European Marie Curie Reintegration Grant, N. Rispail by (FP5) Eufaba project. Our work in this area is supported by Spanish CICYT project AGL-2002-03248 and European Union project FP6-2002-FOOD-1-506223. K. Singh’s work in this area is supported in part by the Grains Research and Development Corporation (GRDC) and the Department of Education, Science and Training (DEST) in Australia.Peer reviewe