Dragon: Multidimensional Range Queries on Distributed Aggregation Trees,

Distributed query processing is of paramount importance in next-generation distribution services, such as Internet of Things (IoT) and cyber-physical systems. Even if several multi-attribute range queries supports have been proposed for peer-to-peer systems, these solutions must be rethought to fully meet the requirements of new computational paradigms for IoT, like fog computing. This paper proposes dragon, an ecient support for distributed multi-dimensional range query processing targeting ecient query resolution on highly dynamic data. In dragon nodes at the edges of the network collect and publish multi-dimensional data. The nodes collectively manage an aggregation tree storing data digests which are then exploited, when resolving queries, to prune the sub-trees containing few or no relevant matches. Multi-attribute queries are managed by linearising the attribute space through space lling curves. We extensively analysed dierent aggregation and query resolution strategies in a wide spectrum of experimental set-ups. We show that dragon manages eciently fast changing data values. Further, we show that dragon resolves queries by contacting a lower number of nodes when compared to a similar approach in the state of the art

Distributed Current Flow Betweeness Centrality

—The computation of nodes centrality is of great importance for the analysis of graphs. The current flow betweenness is an interesting centrality index that is computed by considering how the information travels along all the possible paths of a graph. The current flow betweenness exploits basic results from electrical circuits, i.e. Kirchhoff’s laws, to evaluate the centrality of vertices. The computation of the current flow betweenness may exceed the computational capability of a single machine for very large graphs composed by millions of nodes. In this paper we propose a solution that estimates the current flow betweenness in a distributed setting, by defining a vertex-centric, gossip-based algorithm. Each node, relying on its local information, in a selfadaptive way generates new flows to improve the betweenness of all the nodes of the graph. Our experimental evaluation shows that our proposal achieves high correlation with the exact current flow betweenness, and provides a good centrality measure for large graphs

The Hedgehog-GLI Pathway Regulates MEK5-ERK5 Expression and Activation in Melanoma Cells

Malignant melanoma is the deadliest skin cancer, with a poor prognosis in advanced stages. We recently showed that the extracellular signal-regulated kinase 5 (ERK5), encoded by the MAPK7 gene, plays a pivotal role in melanoma by regulating cell functions necessary for tumour development, such as proliferation. Hedgehog-GLI signalling is constitutively active in melanoma and is required for proliferation. However, no data are available in literature about a possible interplay between Hedgehog-GLI and ERK5 pathways. Here, we show that hyperactivation of the Hedgehog-GLI pathway by genetic inhibition of the negative regulator Patched 1 increases the amount of ERK5 mRNA and protein. Chromatin immunoprecipitation showed that GLI1, the major downstream effector of Hedgehog-GLI signalling, binds to a functional non-canonical GLI consensus sequence at the MAPK7 promoter. Furthermore, we found that ERK5 is required for Hedgehog-GLI-dependent melanoma cell proliferation, and that the combination of GLI and ERK5 inhibitors is more effective than single treatments in reducing cell viability and colony formation ability in melanoma cells. Together, these findings led to the identification of a novel Hedgehog-GLI-ERK5 axis that regulates melanoma cell growth, and shed light on new functions of ERK5, paving the way for new therapeutic options in melanoma and other neoplasms with active Hedgehog-GLI and ERK5 pathways

Inhibition of ERK5 elicits cellular senescence in melanoma via the cyclin-dependent kinase inhibitor p21

2021 The Authors.Melanoma is the deadliest skin cancer with a very poor prognosis in advanced stages. Although targeted and immune therapies have improved survival, not all patients benefit from these treatments. The mitogen-activated protein kinase ERK5 supports the growth of melanoma cells in vitro and in vivo. However, ERK5 inhibition results in cell-cycle arrest rather than appreciable apoptosis. To clarify the role of ERK5 in melanoma growth, we performed transcriptomic analyses following ERK5 knockdown in melanoma cells expressing BRAFV600E and found that cellular senescence was among the most affected processes. In melanoma cells expressing either wild-type or mutant (V600E) BRAF, both genetic and pharmacologic inhibition of ERK5 elicited cellular senescence, as observed by a marked increase in senescence-associated β-galactosidase activity and p21 expression. In addition, depletion of ERK5 from melanoma cells resulted in increased levels of CXCL1, CXCL8, and CCL20, proteins typically involved in the senescence-associated secretory phenotype. Knockdown of p21 suppressed the induction of cellular senescence by ERK5 blockade, pointing to p21 as a key mediator of this process. In vivo, ERK5 knockdown or inhibition with XMD8–92 in melanoma xenografts promoted cellular senescence. Based on these results, small-molecule compounds targeting ERK5 constitute a rational series of prosenescence drugs that may be exploited for melanoma treatment.The work in E. Rovida’s lab was supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC, IG-15282 and IG-21349), by Ente Fondazione Cassa di Risparmio di Firenze (ECRF), and Universita degli Studi di Firenze (Fondo di Ateneo ex-60%). A. Tubita was supported by a “Carlo Zanotti” Fondazione Italiana per la Ricerca sul Cancro (FIRC)-AIRC fellowship (ID-23847)

Insight into immune profile associated with vitiligo onset and anti-tumoral response in melanoma patients receiving anti-PD-1 immunotherapy

IntroductionImmunotherapy with checkpoint inhibitors is an efficient treatment for metastatic melanoma. Development of vitiligo upon immunotherapy represents a specific immune-related adverse event (irAE) diagnosed in 15% of patients and associated with a positive clinical response. Therefore, a detailed characterization of immune cells during vitiligo onset in melanoma patients would give insight into the immune mechanisms mediating both the irAE and the anti-tumor response. MethodsTo better understand these aspects, we analyzed T cell subsets from peripheral blood of metastatic melanoma patients undergoing treatment with anti-programmed cell death protein (PD)-1 antibodies. To deeply characterize the antitumoral T cell response concomitant to vitiligo onset, we analyzed T cell content in skin biopsies collected from melanoma patients who developed vitiligo. Moreover, to further characterize T cells in vitiligo skin lesion of melanoma patients, we sequenced T cell receptor (TCR) of cells derived from biopsies of vitiligo and primary melanoma of the same patient.Results and discussionStratification of patients for developing or not developing vitiligo during anti-PD-1 therapy revealed an association between blood reduction of CD8-mucosal associated invariant T (MAIT), T helper (h) 17, natural killer (NK) CD56bright, and T regulatory (T-reg) cells and vitiligo onset. Consistently with the observed blood reduction of Th17 cells in melanoma patients developing vitiligo during immunotherapy, we found high amount of IL-17A expressing cells in the vitiligo skin biopsy, suggesting a possible migration of Th17 cells from the blood into the autoimmune lesion. Interestingly, except for a few cases, we found different TCR sequences between vitiligo and primary melanoma lesions. In contrast, shared TCR sequences were identified between vitiligo and metastatic tissues of the same patient. These data indicate that T cell response against normal melanocytes, which is involved in vitiligo onset, is not typically mediated by reactivation of specific T cell clones infiltrating primary melanoma but may be elicited by T cell clones targeting metastatic tissues. Altogether, our data indicate that anti-PD-1 therapy induces a de novo immune response, stimulated by the presence of metastatic cells, and composed of different T cell subtypes, which may trigger the development of vitiligo and the response against metastatic tumor

Deregulated expression of the imprinted DLK1-DIO3 region in Glioblastoma Stem-like Cells: tumor suppressor role of lncRNA MEG3

Background: Glioblastoma (GBM) stem-like cells (GSCs) are thought to be responsible for the maintenance and aggressiveness of GBM, the most common primary brain tumor in adults. This study aims at elucidating the involvement of deregulations within the imprinted DLK-DIO3 region on chromosome 14q32 in GBM pathogenesis. Methods: RT-PCR analyses were performed on GSCs and GBM tissues. Methylation analyses, gene expression and Reverse-Phase protein Array profiles were used to investigate the tumor suppressor function of MEG3. Results: Loss of expression of genes and non-coding RNAs within the DLK1-DIO3 region was observed in GSCs and GBM tissues compared to normal brain. This down-regulation is mainly mediated by epigenetic silencing. Kaplan-Meier analysis indicated that low expression of MEG3 and MEG8 lncRNAs significantly correlated with short survival in GBM patients. MEG3 restoration impairs tumorigenic abilities of GSCs in vitro by inhibiting cell growth, migration and colony formation and decreases in vivo tumor growth reducing infiltrative growth. These effects were associated with modulation of genes involved in cell adhesion and Epithelial to Mesenchymal Transition (EMT). Conclusions: In GBM, MEG3 acts as a tumor-suppressor mainly regulating cell adhesion, EMT and cell proliferation, thus providing a potential candidate for novel GBM therapies