Axitinib induces senescence-associated cell death and necrosis in glioma cell lines: The proteasome inhibitor, bortezomib, potentiates axitinib-induced cytotoxicity in a p21(Waf/Cip1) dependent manner.

Glioblastoma is associated with a poor overall survival despite new treatment advances. Antiangiogenic strategies targeting VEGF based on tyrosine kinase inhibitors (TKIs) are currently undergoing extensive research for the treatment of glioma. Herein we demonstrated that the TKI axitinib induces DNA damage response (DDR) characterized by γ-H2AX phosphorylation and Chk1 kinase activation leading to G2/M cell cycle arrest and mitotic catastrophe in U87, T98 and U251 glioma cell lines. Moreover, we found that p21(Waf1/Cip1) increased levels correlates with induction of ROS and senescence-associated cell death in U87 and T98 cell lines, which are reverted by N-acetyl cysteine pretreatment. Conversely, U251 cell line showed a resistant phenotype in response to axitinib treatment, as evidenced by cell cycle arrest but no sign of cell death. The combinatorial use of axitinib with other therapies, with the aim of inhibiting multiple signaling pathways involved in tumor growth, can increase the efficiency of this TKI. Thus, we addressed the combined effects of axitinib with no toxic doses of the proteasome inhibitor bortezomib on the growth of U87 and T98 axitinib- sensitive and axitinib-resistant U251 cell lines. Compared to single treatments, combined exposure was more effective in inhibiting cell viability of all glioma cell lines, although with different cell death modalities. The regulation of key DDR and cell cycle proteins, including Chk1, γ-H2AX and p21(Waf1/Cip1) was also studied in glioma cell lines. Collectively, these findings provide new perspectives for the use of axitinib in combination with Bortezomib to overcome the therapy resistance in gliomas

Capsaicin triggers autophagic cell survival which drives epithelial mesenchymal transition and chemoresistance in bladder cancer cells in an Hedgehog-dependent manner

Bladder cancer (BC) is a common urologic tumor characterized by high risk of recurrence and mortality. Capsaicin (CPS), used as an intravesical drug for overactive bladder, was demonstrated to induce cell death in different cancer cells including BC cells.Here we found that treatment of high-grade BC cells with high dose of CPS triggers autophagy. Infact, the CPS treatment alters the redox homeostasis by inducing production of radicals, mitochondrial depolarization, alterations of ADP/ATP ratio and activation of AMPK pathway stimulating the autophagic process in BC cells. The inhibition of autophagy, by using the specific inhibitor bafilomycin A or Beclin 1 knock-down, enhanced the CPS-induced cell death, demonstrating that CPS-induced autophagy acts as a pro-survival process in BC cells. By using PCR arrays and FACS analysis, we found that the CPS-treated BC cells displayed typical mesenchymal features of the epithelial mesenchymal transition (EMT) as elongated shape and over-expression of vimentin, α5 and β1 integrin subunits, integrin-like kinase and the anti-apoptotic Bcl-2 proteins. Moreover, we demonstrated that CPS treatment stimulates upregulation of Dhh/Ptch2/Zeb2 members of the Hedgehog signaling pathway, increases CD24, VEGFA and TIMP1 and decreases CD44 and ALCAM mRNA expression levels. By PTCH2 knock-down we found that the Hedgehog signaling pathway is involved in the CPS-induced autophagy and EMT phenotype.Finally, we also showed that the CPS-resistant EMT-positive BC cells displayed an increased drug-resistance to the cytotoxic effects of mitomycin C, gemcitabine and doxorubicine drugs commonly used in BC therapy

Advanced radar absorbing ceramic-based materials for multifunctional applications in space environment

In this review, some results of the experimental activity carried out by the authors on advanced composite materials for space applications are reported. Composites are widely employed in the aerospace industry thanks to their lightweight and advanced thermo-mechanical and electrical properties. A critical issue to tackle using engineered materials for space activities is providing two or more specific functionalities by means of single items/components. In this scenario, carbon-based composites are believed to be ideal candidates for the forthcoming development of aerospace research and space missions, since a widespread variety of multi-functional structures are allowed by employing these materials. The research results described here suggest that hybrid ceramic/polymeric structures could be employed as spacecraft-specific subsystems in order to ensure extreme temperature withstanding and electromagnetic shielding behavior simultaneously. The morphological and thermo-mechanical analysis of carbon/carbon (C/C) three-dimensional (3D) shell prototypes is reported; then, the microwave characterization of multilayered carbon-filled micro-/nano-composite panels is described. Finally, the possibility of combining the C/C bulk with a carbon-reinforced skin in a synergic arrangement is discussed, with the aid of numerical and experimental analyses

Country centrality in the international multiplex network

Abstract In this work we introduce and analyze a new and comprehensive multilayer dataset covering a wide spectrum of international relationships between coutries. We select two cross sections of the dataset corresponding to years 2003 and 2010 with 19 layers and 112 nodes to study the structure and evolution of the network. Country centrality is measured by the multiplex PageRank (MultiRank) and the multiplex hub and authority scores (MultiHub and MultiAuth). We find that the MultiHub measure has the highest correlation to GDP per capita, with respect to the other multilayer measures and to their single layer analogues. Finally we analyze the differences in the ranking between GDP per capita and the multilayer centrality measures to evaluate them as measures of development

PRM102 Budget Impact Analysis of Delayed-Release Dimethylfumarate In The Treatment of Relapsing-Remitting Multiple Sclerosis In Italy

INTRODUCTION: Multiple Sclerosis (MS) is a condition with a significant economic and social burden that affects young adults, in their active working phase. The most recent evaluations show an annual average social cost of € 38-39 thousand per patient. Today the approval of the new oral therapies allows physicians to select further options that can meet patients’ clinical unmet needs. OBJECTIVES: To evaluate the economic impact of a recently approved therapy, delayed-release dimethyl-fumarate (DMF; also known as gastro-resistant DMF), on the overall management costs of relapsing-remitting multiple sclerosis (RRMS) in Italy. METHODS: A budget impact model, adopting the perspective of the Italian National Healthcare Service (NHS), was used to compare healthcare costs of two different treatment scenarios: a) base-case, where DMF is not available for RRMS patients (Scenario A), vs. b) alternative-case, where DMF is available for RRMS patients (Scenario B). Healthcare costs sustained by the Italian NHS to manage the RRMS population (drug treatment, administration, therapy and disease monitoring, relapse management, treatment-related adverse events) have been calculated over 3 years and compared for the two scenarios. Impact of relapses for the disease modifying therapies (DMTs) included in the analysis was estimated using an elaboration of the results from published mixed treatment comparison. RRMS population treated with DMTs was estimated using Italian prevalence and incidence data. According to these estimates, the number of treated patients amounted to 36,078 at Year 1, 38,832 at Year 2, and 40,673 at Year 3. RESULTS: According to the current price and to the assumptions reported in the methodology section, it was estimated that the introduction of DMF (Scenario B) determines a decrease of the budget impact, if compared with the base case (Scenario A) in the perspective of Italian NHS. Over three years, the budget impact would be € 1,376 mln in the Scenario A and € 1,354 mln in the Scenario B (-22.18 mln €; -1.61% relative budget variation). The main drivers for cost-saving were pharmacological treatment costs and reduced burden of relapses (corresponding to more than 1,800 avoided relapses). CONCLUSIONS: At the current cost conditions applied in Italy and according to the described assumptions, the use of DMF is economically sustainable for the Italian NHS. Plausibly, the introduction and usage of this new therapy in RRMS patients will ensure clinical benefits for patients without resulting in additional costs for the Italian NHS. [In Italian

Network homophily via multi-dimensional extensions of Cantelli's inequality

Homophily is the principle whereby "similarity breeds connections". We give a quantitative formulation of this principle within networks. We say that a network is homophillic with respect to a given labeled partition of its vertices, when the classes of the partition induce subgraphs that are significantly denser than what we expect under a random labeled partition into classes maintaining the same cardinalities (type). This is the recently introduced \emph{random coloring model} for network homophily. In this perspective, the vector whose entries are the sizes of the subgraphs induced by the corresponding classes, is viewed as the observed outcome of the random vector described by picking labeled partitions at random among partitions with the same type.\,Consequently, the input network is homophillic at the significance level $\alpha$ whenever the one-sided tail probability of observing an outcome at least as extreme as the observed one, is smaller than $\alpha$. Clearly, $\alpha$ can also be thought of as a quantifier of homophily in the scale $[0,1]$. Since, as we show, even approximating this tail probability is an NP-hard problem, we resort multidimensional extensions of classical Cantelli's inequality to bound $\alpha$ from above. This upper bound is the homophily index we propose. It requires the knowledge of the covariance matrix of the random vector, which was not previously known within the random coloring model. In this paper we close this gap by computing the covariance matrix of subgraph sizes under the random coloring model. Interestingly, the matrix depends on the input partition only through its type and on the network only through its degrees. Furthermore all the covariances have the same sign and this sign is a graph invariant. Plugging this structure into Cantelli's bound yields a meaningful, easy to compute index for measuring network homophily

Immigrant entrepreneurs, diasporas, and exports

This paper demonstrates the positive effect of immigrant entrepreneurs on manufacturing exports over and above that of diasporas. Using small\u2010scale regional administrative data, our instrumental variable estimates of export gravity models imply that ceteris paribus, that is, holding constant the total number of immigrants, the expected protrade effect of a migrant becoming an entrepreneur amounts to an average increase of US$5,946 in the export flows toward her country of origin. Besides these dyadic effects, immigrant entrepreneurs unlike nonentrepreneurial immigrants raise a region's overall competitiveness and export flows toward other destinations as well

Some problems with current price indexes

Prices ; Consumer price indexes

CXC and CC chemokines as angiogenic modulators in nonhaematological tumors.

Chemokines are a superfamily of structurally homologous heparin-binding proteins that includes potent inducers and inhibitors of angiogenesis. The imbalance between angiogenic and angiostatic chemokine activities can lead to abnormalities, such as chronic inflammation, dysplastic transformation, and even tumor development and spreading. In this review, we summarize the current literature regarding the role of chemokines as modulators of tumor angiogenesis and their potential role as therapeutic targets in patients with nonhaematological tumors

Transcriptional, epigenetic and pharmacological control of JAK/STAT pathway in NK cells

Differentiation of Natural Killer (NK) cells is a stepwise process having its origin in the bone marrow and proceeding in the periphery, where these cells follow organ specific trajectories. Several soluble factors and cytokines regulate the distinct stages of NK cell differentiation, and ultimately, their functional properties. Cytokines activating the Janus kinases (JAKs) and members of the signal transducer and activator of transcription (STAT) pathway control distinct aspects of NK cell biology, ranging from development, terminal differentiation, activation, and generation of cells with adaptive properties. Here, we discuss how the recent advances of next generation sequencing (NGS) technology have led to unravel novel molecular aspects of gene regulation, with the aim to provide genomic views of how STATs regulate transcriptional and epigenetic features of NK cells during the different functional stages