A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis

Background: Tumor necrosis factor-like weak inducer of apoptosis (Tnfsf12; TWEAK) and its receptor Fibroblast growth factor-inducible 14 (Tnfrsf12a; Fn14) participate in the inflammatory response associated with vascular remodeling.However, the functional effect ofTWEAK on vascular smoothmuscle cells (VSMCs) is not completely elucidated. Methods: Next generation sequencing-based methodswere performed to identify genes and pathways regulated by TWEAK in VSMCs. Flow-citometry, wound-healing scratch experiments and transwellmigration assays were used to analyze VSMCs proliferation and migration. Mouse wire injury model was done to evaluate the role of TWEAK/Fn14 during neointimal hyperplasia. Findings: TWEAK up-regulated 1611 and down-regulated 1091 genes in VSMCs. Using a gene-set enrichment method,we found a functionalmodule involved in cell proliferation defined as the minimal network connecting top TWEAK up-regulated genes. In vitro experiments in wild-type or Tnfrsf12a deficient VSMCs demonstrated that TWEAK increased cell proliferation, VSMCs motility and migration. Mechanistically, TWEAK increased cyclins (cyclinD1), cyclin-dependent kinases (CDK4, CDK6) and decreased cyclin-dependent kinase inhibitors (p15lNK4B) mRNA and protein expression. Downregulation of p15INK4B induced by TWEAK was mediated by mitogen-activated protein kinase ERK and Akt activation. Tnfrsf12a or Tnfsf12 genetic depletion and pharmacological intervention with TWEAK blocking antibody reduced neointimal formation, decreasing cell proliferation, cyclin D1 and CDK4/6 expression, and increasing p15INK4B expression compared with wild type or IgG-treated mice in wire-injured femoral arteries. Finally, immunohistochemistry in human coronary arteries with stenosis or in-stent restenosis revealed high levels of Fn14, TWEAK and PCNA in VSMCs enriched areas of the neointima as compared with healthy coronary arteries. Interpretation: Our data define a major role of TWEAK/Fn14 in the control of VSMCs proliferation and migration during neointimal hyperplasia after wire injury in mice, and identify TWEAK/Fn14 as a potential target for treating in-stent restenosis.This work was supported by Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias ISCiii/FEDER PI13/00395; PI16/01419; PI17/ 01495) and Spanish Biomedical Research Centre in Cardiovascular Disease (CIBERCV) and Metabolic Diseases and Diabetes (CIBERDEM). PM was supported by ISCIII Miguel Servet Program (CP16/00116). CGM was supported by Fundación Conchita Rábago. NMB and VE were supported by the Spanish Ministry of Economy and Competitiveness (Juan de la Cierva IJCI-2016-29630 and Ramón y Ramón Cajal Program RyC-2013-12880, respectively). JMM has been supported a postdoctoral fellowship fromthe American Diabetes Association (Grant 1-15-MI-03) and a postdoctoral fellowship fromthe American Heart Association

Force, charge, and conductance of an ideal metallic nanowire

The conducting and mechanical properties of a metallic nanowire formed at the junction between two macroscopic metallic electrodes are investigated. Both two- and three-dimensional wires with a W(ide)-N(arrow)-W(ide) geometry are modelled in the free-electron approximation with hard-wall boundary conditions. Tunneling and quantum-size effects are treated exactly using the scattering matrix formalism. Oscillations of order E_F/lambda_F in the tensile force are found when the wire is stretched to the breaking point, which are synchronized with quantized jumps in the conductance. The force and conductance are shown to be essentially independent of the width of the wide sections (electrodes). The exact results are compared with an adiabatic approximation; the later is found to overestimate the effects of tunneling, but still gives qualitatively reasonable results for nanowires of length L>>lambda_F, even for this abrupt geometry. In addition to the force and conductance, the net charge of the nanowire is calculated and the effects of screening are included within linear response theory. Mesoscopic charge fluctuations of order e are predicted which are strongly correlated with the mesoscopic force fluctuations. The local density of states at the Fermi energy exhibits nontrivial behavior which is correlated with fine structure in the force and conductance, showing the importance of treating the whole wire as a mesoscopic system rather than treating only the narrow part.Comment: 23 pages, 8 figure

MIBiG 3.0: a community-driven effort to annotate experimentally validated biosynthetic gene clusters

Microbial Biotechnolog

La renovación de la palabra en el bicentenario de la Argentina : los colores de la mirada lingüística

El libro reúne trabajos en los que se exponen resultados de investigaciones presentadas por investigadores de Argentina, Chile, Brasil, España, Italia y Alemania en el XII Congreso de la Sociedad Argentina de Lingüística (SAL), Bicentenario: la renovación de la palabra, realizado en Mendoza, Argentina, entre el 6 y el 9 de abril de 2010. Las temáticas abordadas en los 167 capítulos muestran las grandes líneas de investigación que se desarrollan fundamentalmente en nuestro país, pero también en los otros países mencionados arriba, y señalan además las áreas que recién se inician, con poca tradición en nuestro país y que deberían fomentarse. Los trabajos aquí publicados se enmarcan dentro de las siguientes disciplinas y/o campos de investigación: Fonología, Sintaxis, Semántica y Pragmática, Lingüística Cognitiva, Análisis del Discurso, Psicolingüística, Adquisición de la Lengua, Sociolingüística y Dialectología, Didáctica de la lengua, Lingüística Aplicada, Lingüística Computacional, Historia de la Lengua y la Lingüística, Lenguas Aborígenes, Filosofía del Lenguaje, Lexicología y Terminología

TEN-YEAR SAFETY AND EFFICACY ANALYSES OF THE BIG 02-98 PHASE III TRIAL WITH AN EXPLORATORY ANALYSIS ON THE ROLE OF KI67 IN PREDICTING BENEFIT OF ADJUVANT DOCETAXEL IN ER POSITIVE PATIENTS

Aim: The BIG 2-98 is a randomized phase III trial that tested the effect of adding docetaxel with anthracycline-based adjuvant chemotherapy (CT) in women with node-positive breast cancer (BC). here we present the 10 year safety and efficacy analyses and report an exploratory analysis of the predictive value of Ki67 for docetaxel efficacy. Methods: In total, 2,887 patients with node positive BC were randomly assigned to one of four treatments: (I) sequential control: doxorubicin (A, 75 mg/m2) × 4 → CMF; (II) concurrent control: AC × 4 → CMF; (III) A × 3 → docetaxel (T, 100 mg/m2) × 3 → CMF and (IV) : AT (50/75 mg/m2) × 4 → CMF. The primary objective was to evaluate the efficacy of docetaxel regardless of the schedule on disease free survival (DFS). Secondary objectives were toxicity, DFS between sequential arms and concurrent arms, and overall survival (OS). Ki67 expression was centrally evaluated by immunohistochemistry. Tumours with Ki67 ≥14% were considered to have a high proliferation index. Results: After a median follow-up 10.1 years (max 12.9 years) and 1,072 DFS events, docetaxel treatment did not improve DFS or OS compared to control arms (DFS: HR = 0.91, 95% CI = 0.81-1.04; P = 0.16; OS: HR = 0.88, 95% CI = 0.76-1.03; P = 0.11). Similar results were obtained in secondary comparisons where sequential docetaxel was compared with sequential control (DFS: HR = 0.86, 95% CI = 0.72-1.03, P = 0.1; OS: HR = 0.85, 95% CI = 0.68-1.06; P = 0.15) or with concurrent doxorubicin– docetaxel (DFS: HR = 0.88, 95% CI = 0.7-1.01; P = 0.09; OS: HR = 0.84, 95% CI = 0.7-1.01; P = 0.06). Worsening or development of treatment-related neurotoxicity following completion of adjuvant chemotherapy occurred in 1.6% and 1% of patients in the docetaxel and non-docetaxel-based regimens, respectively. Out of 1,492 patients with ER positive BC, central Ki67 evaluation was performed in 1,198 (80.2%), of whom 892 (74.4%) had Ki67 ≥ 14%. In a multivariate model, there was a trend for improved DFS and OS in patients with high Ki67 and treated with docetaxel (HR = 0.79,95% CI = 0.63-1.01; P = 0.05 and HR = 0.76,95% CI = 0.57-1.01; P = 0.06 respectively). Conclusions: At a median follow-up of 10 years, the DFS benefit previously demonstrated with docetaxel is no longer present in node-positive BC patients. However, an exploratory analysis suggested a benefit of docetaxel in patients with highly proliferative ER-positive BC. Disclosure: P. Francis: Travel support from Sanofi; J.P. Crown: Received research funding and speaking honoraria from Sanofi Aventis; M. Piccart: Board member: PharmaMar Consultant (honoraria) : Amgen, Astellas, AstraZeneca, Bayer, Eli Lilly, Invivis, MSD, Novartis, Pfizer, Roche-Genentech, sanofi Aventis, Symphogen, Synthon, Verastem Research grants to my Institute : most companies. All other authors have declared no conflicts of interest