Primary vascular bone tumors in the spine: a challenge for pathologists and spine oncology surgeons

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A European regulatory perspective on cystic fibrosis: current treatments, trends in drug development and translational challenges for CFTR modulators

In this article we analyse the current authorised treatments and trends in early drug development for cystic fibrosis (CF) in the European Union for the time period 2000–2016. The analysis indicates a significant improvement in the innovation and development of new potential medicines for CF, shifting from products that act on the symptoms of the disease towards new therapies targeting the cause of CF. However, within these new innovative medicines, results for CF transmembrane conductance regulator (CFTR) modulators indicate that one major challenge for turning a CF concept product into an actual medicine for the benefit of patients resides in the fact that, although pre-clinical models have shown good predictability for certain mutations, a good correlation to clinical end-points or biomarkers (e.g. forced expiratory volume in 1 s and sweat chloride) for all mutations has not yet been achieved. In this respect, the use of alternative end-points and innovative nonclinical models could be helpful for the understanding of those translational discrepancies. Collaborative endeavours to promote further research and development in these areas as well as early dialogue with the regulatory bodies available at the European competent authorities are recommended

Identification of stably expressed reference small non-coding RNAs for microRNA quantification in high-grade serous ovarian carcinoma tissues

MicroRNAs (miRNAs) belong to a family of small non‐coding RNAs (sncRNAs) playing important roles in human carcinogenesis. Multiple investigations reported miRNAs aberrantly expressed in several cancers, including high‐grade serous ovarian carcinoma (HGS‐OvCa). Quantitative PCR is widely used in studies investigating miRNA expression and the identification of reliable endogenous controls is crucial for proper data normalization. In this study, we aimed to experimentally identify the most stable reference sncRNAs for normalization of miRNA qPCR expression data in HGS‐OvCa. Eleven putative reference sncRNAs for normalization (U6, SNORD48, miR‐92a‐3p, let‐7a‐5p, SNORD61, SNORD72, SNORD68, miR‐103a‐3p, miR‐423‐3p, miR‐191‐5p, miR‐16‐5p) were analysed on a total of 75 HGS‐OvCa and 30 normal tissues, using a highly specific qPCR. Both the normal tissues considered to initiate HGS‐OvCa malignant transformation, namely ovary and fallopian tube epithelia, were included in our study. Stability of candidate endogenous controls was evaluated using an equivalence test and validated by geNorm and NormFinder algorithms. Combining results from the three different statistical approaches, SNORD48 emerged as stably and equivalently expressed between malignant and normal tissues. Among malignant samples, considering groups based on residual tumour, miR‐191‐5p was identified as the most equivalent sncRNA. On the basis of our results, we support the use of SNORD48 as best reference sncRNA for relative quantification in miRNA expression studies between HGS‐OvCa and normal controls, including the first time both the normal tissues supposed to be HGS‐OvCa progenitors. In addition, we recommend miR‐191‐5p as best reference sncRNA in miRNA expression studies with prognostic intent on HGS‐OvCa tissues

Graphene Oxide Upregulates the Homeostatic Functions of Primary Astrocytes and Modulates Astrocyte-to-Neuron Communication

Graphene-based materials are the focus of intense research efforts to devise novel theranostic strategies for targeting the central nervous system. In this work, we have investigated the consequences of long-term exposure of primary rat astrocytes to pristine graphene (GR) and graphene oxide (GO) flakes. We demonstrate that GR/GO interfere with a variety of intracellular processes as a result of their internalization through the endolysosomal pathway. Graphene-exposed astrocytes acquire a more differentiated morphological phenotype associated with extensive cytoskeletal rearrangements. Profound functional alterations are induced by GO internalization, including the upregulation of inward-rectifying K+ channels and of Na+-dependent glutamate uptake, which are linked to the astrocyte capacity to control the extracellular homeostasis. Interestingly, GO-pretreated astrocytes promote the functional maturation of co-cultured primary neurons by inducing an increase in intrinsic excitability and in the density of GABAergic synapses. The results indicate that graphene nanomaterials profoundly affect astrocyte physiology in vitro with consequences for neuronal network activity. This work supports the view that GO-based materials could be of great interest to address pathologies of the central nervous system associated with astrocyte dysfunctions

RNA Nanotherapeutics for the Amelioration of Astroglial Reactivity.

In response to injuries to the CNS, astrocytes enter a reactive state known as astrogliosis, which is believed to be deleterious in some contexts. Activated astrocytes overexpress intermediate filaments including glial fibrillary acidic protein (GFAP) and vimentin (Vim), resulting in entangled cells that inhibit neurite growth and functional recovery. Reactive astrocytes also secrete inflammatory molecules such as Lipocalin 2 (Lcn2), which perpetuate reactivity and adversely affect other cells of the CNS. Herein, we report proof-of-concept use of the packaging RNA (pRNA)-derived three-way junction (3WJ) motif as a platform for the delivery of siRNAs to downregulate such reactivity-associated genes. In vitro, siRNA-3WJs induced a significant knockdown of Gfap, Vim, and Lcn2 in a model of astroglial activation, with a concomitant reduction in protein expression. Knockdown of Lcn2 also led to reduced protein secretion from reactive astroglial cells, significantly impeding the perpetuation of inflammation in otherwise quiescent astrocytes. Intralesional injection of anti-Lcn2-3WJs in mice with contusion spinal cord injury led to knockdown of Lcn2 at mRNA and protein levels in vivo. Our results provide evidence for siRNA-3WJs as a promising platform for ameliorating astroglial reactivity, with significant potential for further functionalization and adaptation for therapeutic applications in the CNS.The authors wish to acknowledge J. Bernstock and G. Pluchino for their critical insights throughout the execution of the study. This work was funded by the European Research Council (ERC) under the ERC-2010-StG grant agreement n° 260511-SEM_SEM, the Bascule Charitable Trust (RG 75149 to SP), the International Foundation for Research in Paraplegia (RG 69318 to S.P.), Wings for Life (RG 82921 to S.P.) and a core support grant from the Wellcome Trust and Medical Research Council to the Wellcome Trust – MRC Cambridge Stem Cell Institute. LPJ was supported by a research training fellowship from the Wellcome Trust (RRZA/057 RG79423)

An Increase in Membrane Cholesterol by Graphene Oxide Disrupts Calcium Homeostasis in Primary Astrocytes

The use of graphene nanomaterials (GNMs) for biomedical applications targeted to the central nervous system is exponentially increasing, although precise information on their effects on brain cells is lacking. In this work, the molecular changes induced in cortical astrocytes by few-layer graphene (FLG) and graphene oxide (GO) flakes are addressed. The results show that exposure to FLG/GO does not affect cell viability or proliferation. However, proteomic and lipidomic analyses unveil alterations in several cellular processes, including intracellular Ca2+ ([Ca2+ ]i ) homeostasis and cholesterol metabolism, which are particularly intense in cells exposed to GO. Indeed, GO exposure impairs spontaneous and evoked astrocyte [Ca2+ ]i signals and induces a marked increase in membrane cholesterol levels. Importantly, cholesterol depletion fully rescues [Ca2+ ]i dynamics in GO-treated cells, indicating a causal relationship between these GO-mediated effects. The results indicate that exposure to GNMs alters intracellular signaling in astrocytes and may impact astrocyte-neuron interactions

Spinal surgery complications: an unsolved problem—Is the World Health Organization Safety Surgical Checklist an useful tool to reduce them?

Abstract Purpose To investigate whether the World Health Organization Safety Surgical Checklist (SSC) is an effective tool to reduce complications in spinal surgery. Methods We retrospectively evaluated the clinical and radiological charts prospectively collected from patients who underwent a spinal surgery procedure from January 2010 to December 2012. The aim of this study was to compare the incidence of complications between two periods, from January to December 2010 (without checklist) and from January 2011 and December 2012 (with checklist), in order to assess the checklist's effectiveness. Results The sample size was 917 patients with an average of 30-month follow-up. The mean age was 52.88 years. The majority of procedures were performed for oncological diseases (54.4%) and degenerative diseases (39.8%). In total, 159 complications were detected (17.3%). The overall incidence of complications for trauma, infectious pathology, oncology, and degenerative disease was 22.2%, 19.2%, 18.4%, and 15.3%, respectively. No correlation was observed between the type of pathology and the complication incidence. We observed a reduction in the overall incidence of complications following the introduction of the SSC: In 2010 without checklist, the incidence of complications was 24.2%, while in 2011 and 2012, following the checklist introduction, the incidence of complications was 16.7% and 11.7%, respectively (mean 14.2%). Conclusions The SSC seems to be an effective tool to reduce complications in spinal surgery. We propose to extend the use of checklist system also to the preoperative and postoperative phases in order to further reduce the incidence of complications. Graphic abstract These slides can be retrieved under Electronic Supplementary Material

The imprint of a symbiotic binary progenitor on the properties of Kepler's supernova remnant

We present a model for the Type Ia supernova remnant (SNR) of SN 1604, also known as Kepler's SNR. We find that its main features can be explained by a progenitor model of a symbiotic binary consisting of a white dwarf and an AGB donor star with an initial mass of 4-5 M_sun. The slow, nitrogen rich wind emanating from the donor star has partially been accreted by the white dwarf, but has also created a circumstellar bubble. Based on observational evidence, we assume that the system moves with a velocity of 250 km/s. Due to the systemic motion the interaction between the wind and the interstellar medium has resulted in the formation of a bow shock, which can explain the presence of a one-sided, nitrogen rich shell. We present two-dimensional hydrodynamical simulations of both the shell formation and the SNR evolution. The SNR simulations show good agreement with the observed kinematic and morphological properties of Kepler's SNR. Specifically, the model reproduces the observed expansion parameters (m=V/(R/t)) of m=0.35 in the north and m=0.6 in the south of Kepler's SNR. We discuss the variations among our hydrodynamical simulations in light of the observations, and show that part of the blast wave may have traversed through the one-sided shell completely. The simulations suggest a distance to Kepler's SNR of 6 kpc, or otherwise require that SN 1604 was a sub-energetic Type Ia explosion. Finally, we discuss the possible implications of our model for Type Ia supernovae and their remnants in general.Comment: 13 pages, 9 figures. Submitted to A&

INFN ScienzaPerTutti: 20 years of science for society

A groundbreaking and ambitious project took shape within the Istituto Nazionale di Fisica Nuclare (INFN) community 20 years ago. The driving aim was the intent to popularize physics, and all this started through a web portal. Since then, the general public and, in particular, students and teachers have been engaged with cutting edge topics of modern research in particle and nuclear physics, astroparticle, theoretical and applied physics. During the 20 years from its birth, the ScienzaPerTutti project evolved in many different directions, becoming a reference point in the Italian landscape, with an average of 3000 contacts every day on the web pages and thousands of followers on the facebook profile. The project encompasses a variety of multimedia products like didactic units, research materials, infographics, interviews, book reviews, and, more recently, podcasts. A particular feature of many of these activities is a constant call to action to directly involve the audience, providing a continuous challenge for the ScienzaPerTutti editorial board to improve contents and devise new approaches. This contribution focuses on some of these activities, even if it does not provide an exhaustive description of all the programmes and opportunities that are offered to our public for lack of space. Finally, we provide an outlook on new activities