The Effect of Electrospun Gelatin Fibers Alignment on Schwann Cell and Axon Behavior and Organization in the Perspective of Artificial Nerve Design

Electrospun fibrous substrates mimicking extracellular matrices can be prepared by electrospinning, yielding aligned fibrous matrices as internal fillers to manufacture artificial nerves. Gelatin aligned nano-fibers were prepared by electrospinning after tuning the collector rotation speed. The effect of alignment on cell adhesion and proliferation was tested in vitro using primary cultures, the Schwann cell line, RT4-D6P2T, and the sensory neuron-like cell line, 50B11. Cell adhesion and proliferation were assessed by quantifying at several time-points. Aligned nano-fibers reduced adhesion and proliferation rate compared with random fibers. Schwann cell morphology and organization were investigated by immunostaining of the cytoskeleton. Cells were elongated with their longitudinal body parallel to the aligned fibers. B5011 neuron-like cells were aligned and had parallel axon growth when cultured on the aligned gelatin fibers. The data show that the alignment of electrospun gelatin fibers can modulate Schwann cells and axon organization in vitro, suggesting that this substrate shows promise as an internal filler for the design of artificial nerves for peripheral nerve reconstruction

Metastatic breast cancer subtypes and central nervous system metastases

e11581 Background: The relapse pattern, survival and response to therapy are known to be different between breast cancer (BC) subtypes defined by combining hormone-receptor (HR) and HER2 status. Our aim was to study incidence and predictors of central nervous system metastases (CNS-M) and the outcome after CNS-M according to tumor subtype. Methods: 488 patients (pts) treated with at least one line of chemotherapy for metastatic BC were retrospectively evaluated. According to the combination of HR and HER2 status, tumors were grouped in: Luminal (Lum): HR+/HER2-, Luminal/HER2+ (Lum/HER2+): HR+/HER2+, pure HER2 positive (pHER2+): HR-/HER2+, and triple negative (TN): HR-/HER2-. All HER2+ patients received treatment with Lapatinib or Trastuzumab in addition to chemotherapy for metastatic disease. Median follow up was 34 months. Results: 133 pts (27%) developed CNS-M, with a median time to CNS progression of 43 months. The rate of CNS-M by subtype was: Lum 18%, Lum/HER2+ 37%, pHER2+ 49%, TN 25% (p <0.001). Multivariate analysis confirmed that, compared with Lum tumors, Lum/HER2+ ( HR 2.556, p<0.001), pHER2+ (HR 4.444, p<0.001) and TN (2.249, p=0.011) subtypes were at higher risk of CNS-M. Median overall survival (OS) CNS-M was 8.8 months in the whole series (IC 95% 6.6-11.0). Median OS in months by subtype was: Lum 9, Lum/HER2+ 18, pHER2+ 7, TN 7 (p<0.001). Multivariate analysis revealed that belonging to the Lum/HER2+ subtype (HR 0.528 compared with the Lum subtype, p<0.001) and having isolated CNS (HR 0.398, compared with CNS-M plus systemic progression, p<0.001) predicted significantly reduced risk of death. Conclusions: Among pts with a known increased risk of brain metastases, the Lum/HER2+ subtype appears associated with the longest OS after CNS-M, probably due to different biology and better extracranial disease control by chemotherapy, hormonal therapy and target agents. These results suggest that these patients may benefit from a more aggressive treatment of CNS-M and, possibly, from the screening for asymptomatic CNS lesions

Early Paleozoic accretionary orogens along the Western Gondwana margin

Early Paleozoic accretionary orogens dominated the Western Gondwana margin and were characterized by nearly continuous subduction associated with crustal extension and back-arc basin development. The southwestern margin is represented by Famatinian and Pampean basement realms exposed in South America, both related to the protracted Paleozoic evolution of the Terra Australis Orogen, whereas the northwestern margin is mainly recorded in Cadomian domains of Europe and adjacent regions. However, no clear relationships between these regions were so far established. Based on a compilation and reevaluation of geological, paleomagnetic, petrological, geochronological and isotopic evidence, this contribution focuses on crustal-scale tectonic and geodynamic processes occurring in Western Gondwana accretionary orogens, aiming at disentangling their common Early Paleozoic evolution. Data show that accretionary orogens were dominated by high-temperature/low-pressure metamorphism and relatively high geothermal gradients, resulting from the development of extended/hyperextended margins and bulk transtensional deformation. In this sense, retreating-mode accretionary orogens characterized the Early Paleozoic Gondwana margin, though short-lived pulses of compression/transpression also occurred. The existence of retreating subduction zones favoured mantle-derived magmatism and mixing with relatively young (meta)sedimentary sources in a thin continental crust. Crustal reworking of previous forearc sequences due to trenchward arc migration thus took place through assimilation and anatexis in the arc/back-arc regions. Therefore, retreating-mode accretionary orogens were the locus of Early Paleozoic crustal growth in Western Gondwana, intimately associated with major flare-up events, such as those related to the Cadomian and Famatian arcs. Slab roll back, probably resulting from decreasing convergence rates and plate velocities after Gondwana assembly, was a key factor for orogen-scale geodynamic processes. Coupled with synchronous oblique subduction and crustal-scale dextral deformation, slab roll back might trigger toroidal mantle flow, thus accounting for bulk dextral transtension, back-arc extension/transtension and a large-scale anticlockwise rotation of Gondwana mainland.Fil: Oriolo, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires; ArgentinaFil: Schulz, Bernhard. Technische Universität Bergakademie Freiberg; AlemaniaFil: Geuna, Silvana Evangelina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires; ArgentinaFil: Gonzalez, Pablo Diego. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Río Negro. Sede Alto Valle. Instituto de Investigaciones en Paleobiología y Geología; ArgentinaFil: Otamendi, Juan Enrique. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Ciencias de la Tierra, Biodiversidad y Ambiente - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Ciencias de la Tierra, Biodiversidad y Ambiente; ArgentinaFil: Sláma, Jiří. The Czech Academy of Sciences. Institute of Geology; República ChecaFil: Druguet, Elena. Universitat Autònoma de Barcelona; EspañaFil: Siegesmund, Siegfried. Universität Göttingen; Alemani

Modulation of the Neuregulin 1/ErbB system after skeletal muscle denervation and reinnervation

Abstract Neuregulin 1 (NRG1) is a growth factor produced by both peripheral nerves and skeletal muscle. In muscle, it regulates neuromuscular junction gene expression, acetylcholine receptor number, muscle homeostasis and satellite cell survival. NRG1 signalling is mediated by the tyrosine kinase receptors ErbB3 and ErbB4 and their co-receptors ErbB1 and ErbB2. The NRG1/ErbB system is well studied in nerve tissue after injury, but little is known about this system in skeletal muscle after denervation/reinnervation processes. Here, we performed a detailed time-course expression analysis of several NRG1 isoforms and ErbB receptors in the rat superficial digitorum flexor muscle after three types of median nerve injuries of different severities. We found that ErbB receptor expression was correlated with the innervated state of the muscle, with upregulation of ErbB2 clearly associated with the denervation state. Interestingly, the NRG1 isoforms were differently regulated depending on the nerve injury type, leading to the hypothesis that both the NRG1α and NRG1β isoforms play a key role in the muscle reaction to injury. Indeed, in vitro experiments with C2C12 atrophic myotubes revealed that both NRG1α and NRG1β treatment influences the best-known atrophic pathways, suggesting that NRG1 might play an anti-atrophic role